Generally linear effervescent oral fentanyl dosage form and methods of administering

ABSTRACT

Fentanyl containing dosage forms and methods using same are described. These dosage forms include substantially less fentanyl by weight than know oral formulation and have advantages in terms of cost and side effects. These dosage forms are intended for oral administration of fentanyl across the oral mucosa.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the filing date of U.S.Provisional Patent Application Nos. 60/533,619, filed Dec. 31, 2003, and60/615,665, filed Oct. 4, 2004, the disclosures of which are herebyincorporated herein by reference.

BACKGROUND OF THE INVENTION

Fentanyl (CAS Registry No. 437-38-7)N-phenyl-N-[1-(2-phenyl-ethyl)-4-piperidinyl] propanamide and its salts,in particular its citrate salt (CAS Registry No. 990-73-8) are opiates,controlled substances, and extremely potent narcotic analgesics.Fentanyl and its citrate salt are currently marketed by a number ofcompanies in a number of delivery formats. Fentanyl citrate, forexample, is available as an injectable and an oral lozenge on a stick,the latter sold under the trade name ACTIQ. Three patents are identifiedin the FDA publication Approved Drug Products With TherapeuticEquivalence Evaluations (hereinafter “the Orange Book”) as relating toACTIQ: U.S. Pat. Nos. 4,671,953, 4,863,737 and 5,785,989. A second formof ACTIQ may also be available. This form may be a compressed tablet ona stick. Like the original ACTIQ lozenge, this second form is believedto exhibit the same disintegration rate, T_(max), C_(max) and AUC as theoriginal lozenge. Accordingly, they will be discussed collectively,except where expressly stated otherwise or as the context dictates.

A review of the package insert information for ACTIQ sold by Cephalon,Inc., 145 Brandy Wine Parkway West, Chester, Pa. 19380, available in thePhysician's Desk Reference, 57th ed. 2003 at page 1184, brings instantperspective on the seriousness of the afflictions of the patients whotake it. According to its label, ACTIQ “is indicated only for themanagement of break-through cancer pain in patients with malignancieswho are already receiving and who are tolerant to opiate therapy fortheir underlying persistent cancer pain.” (Id., emphasis in original).The text of the ACTIQ label is hereby incorporated by reference.

In clinical trials of ACTIQ, breakthrough cancer pain was defined as atransient flare of moderate-to-severe pain occurring in cancer patientsexperiencing persistent cancer pain otherwise controlled withmaintenance doses of opiate medications, including at least 60 mg ofmorphine/day, 50 micrograms transdermal fentanyl/hour or equianalgesicdose of another opiate for a week or longer. Thus patients receivingACTIQ are patients with suddenly intolerable pain, which flares updespite undergoing chronic analgesic treatment. Providing pain relieffrom such breakthrough pain is inexorably linked with the patient'simmediate quality of life. And for such patients, providing breakthroughpain relief may be the only thing that medical science can offer.

As with many things in medicine, there is always room for improvement.Fentanyl is an expensive drug, costing manufacturers as much as$100/gram or more. While cost is by no means an overriding issue, thecost of medication is an issue to be considered. A formulation thatallows for a reduction in the amount of fentanyl could reduce theoverall cost of a patient's care.

Far more importantly, a reduction in dose of such a potent opiate whilestill achieving beneficial management of breakthrough pain in cancerpatients, has very far reaching and desirable consequences in terms ofpatients overall care. Opiate mu-receptor agonists, including fentanyl,produce dose dependent respiratory depression. Serious or fatalrespiratory depression can occur, even at recommended doses, invulnerable individuals. As with other potent opiates, fentanyl has beenassociated with cases of serious and fatal respiratory depression inopiate non-tolerant individuals. Thus, the initial dose of ACTIQ used totreat episodes of breakthrough cancer patients should be 200 microgramsand each patient should be individually titrated to provide adequateanalgesia while minimizing side effects. And the side effects, eventhose that are not life threatening, can be significant.

In addition, fentanyl, as a mu-opiate agonist can produce drugdependence and tolerance. Drug dependence in and of itself is notnecessarily a problem with these types of cancer patients. But, fentanylcan be used in the treatment of other types of pain as well. In suchtreatment protocols, dependence and tolerance may be significant issues.Moreover, cancer patients are generally undergoing heavy medication. Thelonger that a lower dose of medication can be provided, the better.

U.S. Pat. No. 6,200,604, which issued Mar. 13, 2001 to CIMA LABS INC.,10000 Valley View Road, Eden Prairie, Minn. 55344, exemplifies twofentanyl formulations each containing 36% effervescence and 1.57milligrams of fentanyl salt. See example I thereof, col. 5, ln. 60through col. 6, ln. 30. The '604 patent describes the use of, amongstother things, effervescence as a penetration enhancer for influencingoral drug absorption. See also U.S. Pat. Nos. 6,759,059 and 6,680,071.See also Brendenberg, S., 2003 New Concepts in Administration of Drugsin Tablet Form: Formulation and Evaluation of a Sublingual Tablet forRapid Absorption, and Presentation of an Individualized DoseAdministration System, Acta Universitiatis Upsaliensis. ComprehensiveSummaries of Uppsala Dissertations from the Faculty of Pharmacy, 287, 83pp. Uppsala ISBN 91-554-5600-6.

If lower doses of fentanyl which nonetheless provide similar pain reliefcould be achieved, patients could obtain comparable benefit with muchless drug at lower cost and with a reduced risk of side effects. Thus,improvement in the administration of fentanyl is still desirable.

SUMMARY OF THE INVENTION

The present invention relates to an orally disintegrable/dissolvabledosage form, methods of making such dosage forms methods of using suchdosage forms to treat pain and uses for the manufacture of a medicament,wherein fentanyl, or one or more of its pharmaceutically acceptablesalts (where “fentanyl” is recited herein, it should be assumed toinclude all pharmaceutically acceptable salts unless the contextsuggests otherwise) are administered orally at doses containing at leastabout 45% less fentanyl when compared to noneffervescent lollipopformulations (both lozenge and pressed tablets) currently available.Despite the lower dose, these orally disintegrable dosage forms of theinvention should have a C_(max) which is comparable to other dosageforms containing much more, e.g., about twice as much drug. “Comparable”in this context means that the C_(max) of a dosage form of the presentinvention is at least about 75% that of ACTIQ having about twice as muchfentanyl. Thus, if a 400 microgram tablet in accordance with the presentinvention was compared to a 400 microgram ACTIQ lollipop, and both werecompared to an 800 microgram ACTIQ lollipop, the tablet in accordancewith the present invention would have a C_(max) which is at least about75% to about 125% of the C_(max) of the 800 microgram ACTIQ formulation.The 400 microgram ACTIQ formulation will have a much lower C_(max). Thisis true for doses of up to about 800 micrograms based on the weight offentanyl in free form. Note that “about” in this context (doses) means±10%. Thus, about 100 to about 800 μg is 90 to 880 μg. More preferably,“comparable” in the context of the invention may also mean that theC_(max) of a dosage form of the present invention is between about 80and about 120% that of ACTIQ having about twice as much fentanyl byweight. This can also be referred to as being “highly comparable.” Evenmore preferably, “comparable” in the context of the invention may alsomean that the C_(max) of a dosage form of the present invention isbetween about 85 and about 115% that of ACTIQ having about twice as muchfentanyl by weight. This can also be referred to as being “very highlycomparable”.

“Oral dosage form” in the context of the invention preferably excludeslollipop-like lozenges like ACTIQ® and instead includes orallydisintegrable dissolvable tablets, capsules, caplets, gels, creams,films and the like. Preferably, these dosage forms are effervescenttablets. In addition, they may include a pH adjusting substance and adisintegrant. Generally, these dosage forms are applied to or placed ina specific place in the oral cavity and they remain there while theydisintegrate and/or dissolve, generally in a period of about 10 to 30minutes.

In another preferred aspect of the present invention, there is providedan orally disintegrable effervescent dosage form designed for theadministration of fentanyl and/or pharmaceutically acceptable saltsthereof through the oral cavity such as through buccal, gingival orsublingual administration routes, rather than being swallowed. Thisformulation preferably will not include a stick or other such devicepermitting it to be easily held in the hand of a patient or removed fromthe mouth once the dosage form has been wetted in the mouth. Inaddition, the dosage form will include at least about 45% less fentanyl(based on its weight calculated as a free base material) and morepreferably between about 45% and about 55% less fentanyl when comparedto the corresponding ACTIQ® product. Yet they will be comparable,preferably highly comparable and even more preferably very highlycomparable in terms of C_(max), as well as generally equallyefficacious.

Thus, if 1600 micrograms of fentanyl is provided in an ACTIQ®formulation, the corresponding dosage form in accordance with thepresent invention would include approximately 880 micrograms of fentanylor less. More preferably, it would include about 800 micrograms offentanyl. Yet despite such a dramatic reduction in the amount of drug,at least one or more of the traditional pharmacokinetic propertiesmeasured for various drugs, such as C_(max), would be similar, if notsuperior. For example, in accordance with the present invention,formulations may have a shorter T_(max), the time at which the maximumconcentration is reached and/or a comparable, if not superior, C_(max),the highest observed concentration in the blood of a patient afteradministration, when compared to the corresponding ACTIQ® productcontaining at least 80% more fentanyl by weight. AUC or areas under thecurve will generally be linear for dosage forms of increasing fentanylcontent over the dosage ranges contemplated.

In a particularly preferred aspect of the present invention, it has beendiscovered that the formulations can be produced having a roughly linearrelationship between dose of fentanyl (measured by weight as a freebase) and C_(max), specifically, over dose ranges of about 100-800micrograms per dose. “Linear” should be understood to mean that therewill be no significant difference in the dose-normalized C_(max) in thedose of 90 to 880 micrograms (more preferably 100-810 μg) using ANOVAwithin a p of 0.15 (p less than or equal to 0.15) when formulated aspart of a series of at least three dosage forms with varying dosesbetween 90 and 880 micrograms of fentyl. This is the preferred way ofdetermining linearity in accordance with the invention. Stated anotherway, the slope of ln(C_(max)) versus ln(dose) should be 1±15%(0.85-1.15). As noted in studies discussed herein, doses of 200, 500 and810 μg were “linear” in accordance with the present invention. Doses of1080 μg, while vastly superior to the prior art, were not “linear” asdefined herein in terms of C_(max) to dose compared to the other doses.

The ratio of C_(max) to dose in this dosage range is between about 2.0and about 4.0 picograms/mL/microgram. That is picograms of fentanyl baseper mL of serum or a proportionate amount if determined in blood orother fluid, normalized per microgram of the dose. “Between” inaccordance with the present invention includes the endpoints. Morepreferably, the ratio is about 2.5 to about 3.5 and even more preferablybetween about 2.7 and about 3.5 picograms/mL/microgram. These ranges arebased on mean data calculated for at least 10 patents in an appropriateclinical trial. In contrast, testing has established that ACTIQ providesa ratio of about 1.4 picograms/mL/microgram. Thus for dosage formscontaining the same amount of fentanyl, the present invention canprovide about twice the C_(max), if not more, up to doses of 880micrograms, e.g., about 800 micrograms using the invention. In anotherembodiment, these dosage forms would also provide a linear relationshipbetween dose and C_(max) when formulated over a range of about 100 toabout 800 micrograms of fentanyl (free base) or a proportionate amountof salt. Of course, for a single dose strength, this means that theratio of dose and C_(max) for that dose will have a linear relationshipto a series produced by merely varying the same formulation to includemore or less fentanyl over the described range.

Also preferred as one aspect in accordance with the present inventionare effervescent dosage forms of fentanyl designed to be administeredbuccally, gingivally or sublingually containing 880 micrograms or lessof fentanyl, by weight, based on the weight of the free base materialand having a T_(max) of less than about 1.5 hours and most preferablyless than about 1 hour. Yet these dosage forms will have a desirableC_(max) as discussed above of between about 2.0 and about 4.0picograms/mL/microgram. Methods of administering these dosage forms totreat pain are also contemplated.

In a particularly preferred embodiment in accordance with the presentinvention, these formulations include effervescence to act as apenetration enhancer with or without, but preferably with an additionalpH adjusting substance. Most preferably, the pH adjusting substance issomething other than one of the components, compounds or molecules usedto generate effervescence. Particularly preferred dosage forms alsoinclude a disintegrant which permits the dose reduction, linearityand/or ratio of C_(max) and dose described herein. One particularlypreferred example of a disintegrant is a starch glycolate. Alsopreferred are dosage forms including a filler which faciliates the sameperformance as the disintegrants just described. Most preferably thefiller is mannitol.

In a particularly preferred embodiment in accordance with the presentinvention, there is provided an oral dosage form suitable for buccal,sublingual or gingival administration containing up to one milligram,and more preferably 100, 200, 300, 400, 600 or 800 micrograms offentanyl by weight measured as the free base and further including atleast one effervescent couple, at least one pH adjusting substance andsuitable excipients. Preferably such a formulation will be capable ofproviding a T_(max) of 1.5 hours or less and/or a C_(max) between about2.0 and about 4.0 picograms/mL/microgram. Stated another way, theC_(max) of the dosage forms of the present invention are comparable tothe C_(max) of an ACTIQ® formulation containing at least about 80percent more fentanyl by weight. In another preferred embodiment, thesedosage forms will have a C_(max) that is within about 25% of that ofACTIQ® having at least about 80% more fentanyl free base by weight,preferably within about 20% and even more preferably within about 15%thereof.

In another particularly preferred embodiment in accordance with thepresent invention, there is provided an orally disintegrable tabletsuitable for buccal, sublingual or gingival administration containingabout 100, 200, 300, 400, 600 or 800 micrograms of fentanyl, measured asa free base, at least one effervescent couple, and at least one pHadjusting substance, as well as suitable excipients, said dosage formbeing capable of providing a T_(max) of about 1.5 hours or less and/or aC_(max) of between about 2.7 and about 3.5 picograms/mL/microgram.

In yet another embodiment in accordance with the present invention, anyof the formulations previously mentioned herein may consist essentiallyof fentanyl, preferably in an amount of about 800 micrograms or less(i.e., up to 880 μg), an effervescent couple, at least one pH adjustingsubstance and suitable excipients which are capable of providing aC_(max) of between about 2.0 and about 4.0 picograms/mL/microgram, morepreferably between about 2.5 and about 3.5 picograms/mL/microgram, andmost preferably between about 2.7 and about 3.5 picograms/mL/microgramand containing at least about 45% less fentanyl than an ACTIQ® dosageform providing comparable C_(max). In the present context, “consistingessentially of” is meant to exclude any excipient or combination ofexcipients or, as appropriate, any amount of any excipient orcombination of excipients, as well as any pH adjusting substance or anyamount of pH adjusting substance that would alter the basic and novelcharacteristics of the invention. Thus, a particular excipient ormixture of excipients that would increase the T_(max) to 2.5 hours orgreater would be excluded. Similarly, and again for exemplary purposesonly, a combination of excipients provided in a specific amount whichwould alter C_(max) to a level not contemplated would be excluded. Asmall amount of cross-linked PVP and/or lactose monohydrate, whilegenerally undesirable, which would not significantly alter the T_(max)or C_(max) of the dosage forms of the invention could still be used.However, if used together and at levels of 5% and 20% respectively, theycan alter the properties adversely. Thus, these amounts of theseexcipients, in combination, would be excluded.

In a particularly preferred embodiment of this aspect of the presentinvention, there are provided dosage forms consisting essentially of:between 90 and 880 micrograms of fentanyl, calculated as fentanyl freebase, or a salt thereof, sodium starch glycolate, mannitol, at least onepH adjusting substance and at least one effervescent couple. Preferably,these dosage forms provide a T_(max) of about 1.5 hours or less, a ratioof C_(max) to dose of between about 2.0 and about 4.0picograms/mL/microgram, a linear C_(max) with dose, and/or a C_(max)that is comparable as defined herein, the dosage form being suitable forbuccal, sublingual or gingival administration. More preferably, theamount of fentanyl measured as a free base is 100-800 micrograms.

Also contemplated as another aspect of the invention are methods ofadministering fentanyl to patients experiencing pain in generalincluding but not limited to: back pain, lower back pain, joint pain,any form of arthritic pain, pain from trauma or accidents, neuropathicpain, surgical or postoperative pain, pain from a disease or conditionother than cancer, cancer pain and in particular, breakthrough pain as aresult of cancer. A preferred method includes the steps of administeringto a patient in need thereof any orally disintegrable effervescenttablet disclosed herein for buccal, gingival or sublingualadministration, which includes a dose of fentanyl of between about100-800 micrograms (measured as a free base), and holding the dosageform in the mouth of the patient for a time sufficient to allowtransport of said dose (or a therapeutically significant and/oreffective portion thereof) from the oral cavity to the blood stream.Preferably, the patient is instructed, trained or watched to ensure thatthe dose is not swallowed and instead to the extent practicable, thefentanyl enters the body through one or more of the surfaces within themouth and oral cavity. The method also preferably includes the step ofholding the dosage form in the mouth, substantially without moving itwithin the oral cavity. In another preferred aspect, the dosedissolves/disintegrates or has a mean dwell time of between 5 and 30minutes.

One such method is a method of treating episodes of breakthrough cancerpain comprising the steps of providing an initial dose of about 100micrograms of fentanyl calculated as a fentanyl free base or anequivalent amount of a salt thereof, in a dosage form comprising aneffervescent couple in amount of about 5 to about 85% by weight of thedosage form, a pH adjusting substance in an amount of about 0.5 to about25% by weight of the dosage form, and a starch glycolate in the amountof 0.25 to about 20% by weight of the dosage form. The dosage form issuitable for delivery of said fentanyl across the oral mucosa of apatient. By “providing” it is understood that removing a dosage formfrom a package or having someone hand out or dispense such a dosage formare included. The method also includes placing the dosage form in themouth of the patient between the cheek and the upper or lower gum, for atime sufficient to deliver a therapeutically effective amount of saidfentanyl across said oral mucosa. The same method may be employed forthe treatment of other types of pain including any type of back pain,surgical or postoperative pain and neuropathic pain.

It would not have been expected that it would be possible to produce anorally disintegrable tablet designed for administration of fentanyl inthe oral cavity which was capable of providing T_(max) of 1.5 hours orless containing 880 micrograms of fentanyl or less, measured as freebase, preferably having a desirable C_(max). While certain literaturefor the ACTIQ lozenge suggests a T_(max) of about 45 minutes, testinghas shown this to be more like two hours.

It was not expected that it would be possible to produce an orallydisintegrable dosage form designed for administration of fentanyl in theoral cavity through buccal, sublingual or gingival administration routewhich contained at least about 45% less fentanyl than the ACTIQ® dosageform which provided comparable C_(max) data.

It was also not expected that it would be possible to produce an orallydisintegrable dosage form and use it to treat pain, and in particularthe breakthrough pain experienced by cancer patients wherein atheraputically effective amount (an amount which can provide somemeasure of pain relief), generally more than 75%, more preferably morethan 80% and most preferably 90% or more of the fentanyl dose isabsorbed into the blood stream from the oral cavity across the oralmucosa.

It was also not expected that the C_(max) of dosage forms having so muchless active drug compared to currently marketed products could be linearin terms of C_(max) to dose, for example, ±15% confidence interval overa range of about 100 to about 800 μg (90-880 μg).

In accordance with another aspect of the present invention, there isprovided a method of making a buccal, gingival or sublingual,effervescent fentanyl dosage form capable of providing one or more of: alinear relationship between dose and Cmax over a range of about 100 toabout 800 micrograms; a comparable Cmax at a dose of at least about 45%less fentanyl when compared to a non-effervescent formulation such asACTIQ at the same dose; and a ratio of Cmax to dose of 2.0 to 4.0picograms/mL/micrograms. This is accomplished by mixing an amount offentanyl (based on the weight of the free base) of between about 100 toabout 800 micrograms per dosage form with an effective amount of aneffervescent couple, an effective amount of a pH adjusting substancecapable of producing a change in the localized pH in themicroenvironment at the surface contact area of the oral mucosa and thedosage form once placed in the mouth of a patient (“localized pH”), asmeasured as described herein, of at least 0.5 pH units when compared toan identical formulation without the pH adjusting substance, and adisintegrant which permits the dose reduction, linearity and ratio ofCmax and dose as described above. These are compressed into a tablet orotherwise formed into a dosage form using conventional techniques.Perferably this process is accomplished without granulation, althoughthe individual materials used may be granulated before mixing. Thus, awet granulated sugar could be used as a filler in an otherwise dry anddirect compression process.

More preferably, the method is used to make a dosage form, preferably atablet, that produces a linear relationship between dose and Cmax over arange of about 100 to about 800 micrograms, a highly comparable Cmax ata dose of at least about 50% less fentanyl when compared to ACTIQ at thesame dose and/or a ratio of Cmax to dose of between about 2.7 and about3.5 picorgrams/mL/micrograms. This is accomplished by mixing an amountof fentanyl or a salt thereof appropriate to provide a predeterminednumber of dosage forms each having between about 100 and about 800micrograms of fentanyl, an effervescent couple in an amount of about 5to about 85% by weight of the finished dosage forms (w/w), a pHadjusting substance in an amount of between about 0.5 to about 25% w/w,a starch glycolate in an amount of between about 0.25 and about 20% w/wwith or without mannitol, and compressing same into a tablet in a drystate. Preferably, the pH adjusting substance will provide a change inlocalized pH of at least about 1 pH unit when compared to an identicalformulation without same.

DETAILED DESCRIPTION

Throughout the entire specification, including the claims, the word“comprise” and variations of the word, such as “comprising” and“comprises,” as well as “have,” “having,” “includes,” “include” and“including,” and variations thereof, means that the named steps,elements or materials to which it refers are essential, but other steps,elements or materials may be added and still form a construct with thescope of the claim or disclosure. When recited in describing theinvention and in a claim, it means that the invention and what isclaimed is considered to what follows and potentially more. These terms,particularly when applied to claims, are inclusive or open-ended and donot exclude additional, unrecited elements or methods steps.

For purposes of the present invention, unless otherwise defined withrespect to a specific property, characteristic or variable, the term“substantially” as applied to any criteria, such as a property,characteristic or variable, means to meet the stated criteria in suchmeasure such that one skilled in the art would understand that thebenefit to be achieved, or the condition or property value desired ismet.

The present invention includes, in one aspect, a dosage form comprisingbetween about 100 and about 800 μg (micrograms) of fentanyl, calculatedas fentanyl free base, or a salt thereof, suitable for buccal,sublingual or gingival administration. The dosage form, when properlyadministered by contacting it to the oral mucosa for a sufficient time,is capable of providing a T_(max) of 1.5 hours or less. In addition, orinstead, the ratio of C_(max) to dose of between about 2.0 and about4.0, more preferably between about 2.3 and about 3.5 and most preferablybetween about 2.7 and about 3.5 picograms/mL/microgram will be realized.Most preferably, the relationship between dose and C_(max) is linear fordose of between about 100 and about 800 micrograms compared to otherdoses otherwise formulated in the same way.

The dosage form preferably further comprises at least one pH adjustingsubstance and at least one effervescent couple. These are each providedin an amount that is sufficient to provide the desired T_(max) and/orC_(max). The dosage form also preferably comprises at least oneexcipient that is selected and provided in an amount which, incombination with the at least one pH adjusting substance and the atleast one effervescent couple, provide the desired T_(max) and/orC_(max).

A method of administering fentanyl to a patient experiencing pain isanother aspect of the invention. This method can comprise the steps ofcontacting the oral mucosa of a patient in need thereof with an orallydisintegrable, dosage form. The dosage form includes a dose of fentanylof between about 100-800 (90-880) micrograms (measured as a free base),per dosage form, or a salt thereof. The dosage form is capable ofproviding a T_(max) of 1.5 hours or less, and/or a ratio of C_(max) todose of between about 2.0 and about 4.0, more preferably between about2.3 and about 3.5 and most preferably between about 2.7 and about 3.5picograms/mL/microgram and/or a linear relationship between C_(max) anddose, preferably for a dosage form that includes at least 45% lessfentanyl than would otherwise be prescribed using commercially knowndelivery formats. The dosage form is held in contact with the oralmucosa of the patient for a time sufficient to allow transport of atherapeutically significant or effective portion of the fentanyl,preferably more than 75%, more preferably more than 80% and mostpreferably 90% or more of the dose, from the oral cavity to the bloodstream across the oral mucosa.

Another aspect of the invention provides a dosage form comprising:between about 100 and about 800 micrograms of fentanyl per dosage form,calculated as fentanyl free base. A fentanyl salt, when used, is used inan amount providing an equivalent amount of fentanyl free base byweight. The dosage form is suitable for buccal, sublingual or gingivaladministration. The dosage form, when properly administered bycontacting it to the oral mucosa for a sufficient time, is capable ofproviding a C_(max) which is at least about 75 to about 125%, morepreferably between about 80 and about 120%, and most preferably betweenabout 85% to about 115% that of an ACTIQ® formulation wherein the latterincludes at least 80% more fentanyl by weight. Preferably, this dosageform also includes at least one pH adjusting substance and at least oneeffervescent couple in an amount which is sufficient to provide thestated C_(max). Even more preferably, the dosage form further comprisesat least one excipient in an amount which, in combination with the atleast one pH adjusting substance and/or at least one effervescent coupleis sufficient to provide the desired C_(max).

There is also contemplated a method of administering fentanyl to apatient experiencing pain comprising the steps of contacting the oralmucosa of a patient in need thereof with an orally disintegrable, dosageform which includes a dose of fentanyl of between about 100-800micrograms (measured as a free base) per dosage form, or an equivalentamount of a salt thereof. The dosage form exhibits a C_(max) which is atleast about 75% to about 125%, more preferably between about 80 andabout 120%, and most preferably between about 85% to about 115% that ofan ACTIQ® formulation including at least 80% more fentanyl by weight.The dosage form is held in contact with the oral mucosa of the patientfor a time sufficient to allow transport a therapeutically significantor effective portion of the fentanyl, preferably more than 75%, morepreferably more than 80% and most preferably 90% or more of the dose,from the oral cavity to the blood stream across the oral mucosa.

It has now been discovered that the use of effervescence and a pHadjusting substance, particularly when combined with a starch glycolate,can provide significant advantages particular in terms of the amount offentanyl that is required for dosing. It has also been found thatcertain excipients in combination with effervescent couples and pHadjusting substances can provide even better, and very unexpected,results.

Determining whether or not a particular formulation is capable ofachieving the results described herein, one need only undertake aroutine human clinical study of that formulation in at least 10patients. The appropriate clinical study would use any of thetraditional models. Examples of appropriate studies follow:

Clinical Study Design and Conduct

This study and Informed Consent Forms (ICF) were Institutional ReviewBoard (IRB) approved. All subjects read and signed an IRB-approved ICFprior to study initiation. Signed and witnessed ICFs are on file.

For the first two periods the study utilized a single-dose, randomized,open-label, 2-way crossover design of the designated test and referenceproducts, and subjects were randomized to receive one of threeadditional test formulations during Period 3. All subjects wererandomized and were in a fasted state following a 10-hour overnightfast. There was a 7-day washout interval between the three doseadministrations. The subjects were confined to the clinic through 36hours post-fentanyl administration.

The subjects were screened within 21 days prior to study enrollment. Thescreening procedure included medical history, physical examination(height, weight, frame size, vital signs, and ECG), and clinicallaboratory tests (hematology, serum chemistry, urinalysis, HIV antibodyscreen, hepatitis B surface antigen screen, hepatitis C antibody screen,serum pregnancy [females only]), and a screen for cannabinoids andopioids.

All subjects enrolled in the study satisfied the inclusion/exclusioncriteria as listed in the protocol. A total of 42 subjects, 17 males and25 females, were enrolled in the study, and 39 subjects, 17 males and 22females, completed the study.

Subjects reported to the clinic on the morning prior to each dosing andreceived lunch 19 hours prior to dosing, dinner 14 hours prior todosing, and a snack 11 hours prior to dosing. The subjects then observeda 10-hour overnight fast. On Day 1, a standardized meal schedule wasinitiated with lunch at 4.5 hours postdose, dinner at 9.5 hourspostdose, and a snack at 13 hours postdose. On Day 2, breakfast wasserved at 24.5 hours postdose, lunch at 28.5 hours postdose, and dinnerat 33 hours postdose.

The subjects were not to consume any alcohol-, broccoli-, citrus-,caffeine-, or xanthine-containing foods or beverages for 48 hours priorto and during each period of confinement. Subjects were to be nicotine-and tobacco-free for at least 6 months prior to enrolling in the study.In addition, over-the-counter medications were prohibited 7 days priorto dosing and during the study. Prescription medications were notallowed 14 days prior to dosing and during the study (excluding hormonalcontraceptives for females).

During the study, the subjects were to remain seated for 4 hours afterthe fentanyl citrate was administered. Water was restricted from Hour 0until 4 hours postdose. Food was restricted 10 hours predose until 4hours postdose. During the study, the subjects were not allowed toengage in any strenuous activity.

Subjects received naltrexone at each period as detailed below:

-   -   Adm 1: ReVia® 50 mg (naltrexone hydrochloride tablets)        Manufactured by Bristol-Myers Squibb Company        -   Lot No.: 5C269A        -   Expiration date: Apr 2004        -   Lot No.: TB1798        -   Expiration date: Mar 2005

Subjects assigned to Treatments A, B, C, and D received an oral dose ofone 50 mg naltrexone tablet taken with 240 mL of water at 15 hours and 3hours prior to and 12 hours following the fentanyl dose.

Subjects assigned to Treatment E received an oral dose of one 50 mgnaltrexone tablet taken with 240 mL of water at 15 hours and 3 hoursprior to the fentanyl dose.

Subjects received one of the following fentanyl treatments at each of 3periods:

A: OraVescent® Fentanyl Citrate Tablets 1080 μg (as fentanyl base)

-   -   Manufactured by CIMA LABS INC    -   Lot No.: 930502        Subjects randomized to Treatment A received a single oral dose        of one 1080 μg fentanyl tablet placed between the upper gum and        cheek above a molar tooth and allowed to disintegrate for 10        minutes. Note that “OraVescent®” indicates a formulation and        dosage form in accordance with the invention.

B: Actiq® (oral transmucosal fentanyl citrate) equivalent to 1600 μg

-   -   Manufactured by Cephalon, Inc. or Anesta    -   Lot No.: 02 689 W3        Subjects randomized to Treatment B received a single oral dose        of one 1600 μg Actiq® unit placed between the cheek and lower        gum. The unit was to be moved from side to side using the handle        and allowed to dissolve for 15 minutes.

C: OraVescent® Fentanyl Citrate Tablets 1300 μg (as fentanyl base)

-   -   Manufactured by CIMA LABS INC    -   Lot No.: 930503        Subjects randomized to Treatment C received a single oral dose        of one 1300 μg fentanyl tablet placed between the upper gum and        cheek above a molar tooth and allowed to disintegrate for 10        minutes.

D: OraVescent® Fentanyl Citrate Tablets 810 μg (as fentanyl base)

-   -   Manufactured by CIMA LABS INC    -   Lot No.: 930501        Subjects randomized to Treatment D received a single oral dose        of one 810 μg fentanyl tablet placed between the upper gum and        cheek above a molar tooth and allowed to disintegrate for 10        minutes.

E: OraVescent® Fentanyl Citrate Tablets 270 μg (as fentanyl base)

-   -   Manufactured by CIMA LABS INC    -   Lot No.: 930500        Subjects randomized to Treatment E received a single oral dose        of one 270 μg fentanyl tablet placed between the upper gum and        cheek above a molar tooth and allowed to disintegrate for 10        minutes.

The composition of each of these fentanyl citrate tablets is describedin Examples 1-4.

Sitting vital signs (blood pressure, pulse, and respiration) wereassessed each morning prior to dosing (Hour 0) and at 0.25, 0.5, 0.75,1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8,10, 24, and 36 hours postdose. Continuous pulse oximetry was conductedfor the first 8 hours postdose. A 12-lead electrocardiogram, a clinicallaboratory evaluation (hematology, serum chemistry, and urinalysis), anda physical examination with complete vital signs were performed at thecompletion of the study. Oral irritation assessments were conducted 4hours postdose. Subjects were instructed to inform the study physicianand/or nurses of any adverse events that occurred during the study.

Blood samples (7 mL) were collected at the following times for subjectsassigned to Treatments A-D: predose (Hour 0), and 10, 20, 30, and 45minutes; and 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, and 36 hourspostdose. Blood samples (7 mL) were collected at the following times forsubjects assigned to Treatment E: predose (Hour 0), and 10, 20, 30, and45 minutes; and 1, 2, 4, 6, 8, 9, 10, 11, 12, 14, 16, 20, and 24 hourspostdose. A total of 54 blood samples (378 mL) were drawn during thestudy for drug analysis. Samples were collected and processed at roomtemperature under fluorescent lighting. Serum samples were allowed toclot, separated by centrifugation, frozen at −20° C., and kept frozenuntil assayed.

Analytical Methods

An LC-MS/MS (liquid chromatography-mass spectrometry/mass spectrometry)of fentanyl in human serum.

Pharmacokinetic and Statistical Methods

The pharmacokinetic and statistical analysis was based on the Food andDrug Administration, Center for Drug Evaluation and Research (CDER),Guidance for Industry issued January 2001 and entitled “StatisticalApproaches to Establishing Bioequivalence,” and Guidance for Industryissued March 2003 and entitled “Bioavailability and BioequivalenceStudies for Orally Administered Drug Products—General Considerations.”

The following noncompartmental pharmacokinetic parameters were computedfrom the fentanyl concentration-time data for each treatment usingWinNonlin Standard Edition version 2.1. Actual (rather than nominal)sampling times were used in the analysis.

-   AUC(0-t) Area under the fentanyl concentration-time curve calculated    using linear trapezoidal summation from time zero to time t, where t    is the time of the last measurable concentration (Ct).-   AUC(0-inf) Area under the fentanyl concentration-time curve from    time zero to infinity, AUC(0-inf)=AUC(0-t)+Ct/Kel, where Kel is the    terminal elimination rate constant.-   AUC(0-t)/ AUC(0-inf) Ratio of AUC(0-t) to AUC(0-inf). Also referred    to as AUCR.-   AUC(0-tmax) The partial area from time 0 to the median Tmax of the    reference formulation, calculated using linear trapezoidal    summation.-   Kel Terminal elimination rate constant calculated by linear    regression of the terminal linear portion of the log concentration    vs. time curve, where Kel=−slope. The terminal linear portion was    determined by visual inspection.-   T½ Elimination half-life calculated as ln(2)/Kel.-   C_(max) Maximum observed fentanyl concentration.-   T_(max) Time of the maximum fentanyl concentration (obtained without    interpolation).

This study was a single-dose, randomized, open-label, 2-way crossover ofthe designated test and reference products. (Treatment A and TreatmentB, Periods 1 and 2) with subjects randomized to receive one of threeadditional test formulations (Treatment C, Treatment D, or Treatment E)during Period 3. Due to the larger number of subjects, the study was runin two groups. The primary comparison in this study was Treatment Aversus Treatment B. For the analysis of variance comparing these twotreatments, only two sequences (AB, BA), two periods (1, 2), and twotreatments (A, B) were considered.

A parametric (normal-theory) general linear model was applied to thelog-transformed AUC(0-inf), AUC(0-t), and Cmax values from Treatments Aand B.⁵⁻⁷ The full analysis of variance (ANOVA) model considered groupin the model and included the following factors: group, period withingroup, treatment, sequence, sequence by group, subject within sequenceby group, and treatment by group. Since the treatment by groupinteraction was not significant, the model was reduced to sequence,subject within sequence, period, and treatment. The sequence effect wastested using the subject within sequence mean square and all other maineffects were tested using the residual error (error mean square). Thetwo one-sided hypotheses were tested at the 5% level for AUC(0-t),AUC(0-inf), and Cmax by constructing 90% confidence intervals for theratio of the test and reference means (Treatment A versus Treatment B).

Differences in Tmax for Treatment A and Treatment B were evaluated usingthe Wilcoxon Signed Ranks Test (α=0.05).

Serum fentanyl concentrations and pharmacokinetic parameters were alsodetermined following Treatment C, Treatment D, and Treatment E (1300 μg,810 μg, and 270 μg OraVescent® Fentanyl Citrate tablet, respectively).In order to evaluate dose proportionality of the OraVescent® FentanylCitrate formulation, a mixed linear model was applied to thedose-normalized Cmax and AUC parameters from Treatments A, C, D, andE.⁵⁻⁷ The full model considered group and included the following terms:group, period within group, treatment, sequence, sequence by group,subject within sequence by group, and treatment by group. The treatmentby group interaction was not significant for 2 of the 3 parameters [Cmaxand AUC(0-t)] and the model was reduced to a one-way ANOVA with thefactor of treatment. If an overall treatment effect was found, pairwisecomparisons were performed using Treatment A as the reference.

The dwell time values (length of time the formulation was present in theoral cavity) were calculated by subtracting the treatment administrationtime from the time of perceived and documented disappearance of theformulation. These values were tabulated and summary statistics werepresented.

RESULTS

Demographics and Disposition of Subjects

A total of 42 subjects, 17 males and 25 females, were enrolled in thestudy, and 39 subjects, 17 males and 22 females, completed the study.

Three subjects were discontinued/withdrawn from the study. One subjectwas dropped prior to Period 2 because the subject did not want tocontinue on the study. A second subject was dropped prior to Period 3because the subject did not want to continue on the study. A thirdsubject was dropped prior to Period 2 because subject took anantibiotic.

The mean age of the subjects was 27 years (range 19-55 years), the meanheight of the subjects was 68 inches (range 62-74 inches), and the meanweight of the subjects was 152.1 pounds (range 109.0-197.0 pounds).

Protocol Deviations and Adverse Events

The following protocol deviations occurred during the conduct of thestudy.

According to the protocol, subjects were to have respirations taken atthe 3.5-hour vital signs time point. Respirations were not taken at the3.5-hour time point for one subject during Period 2. Vital sign recheckwas not performed at the 3-hour time point of Period 2 for two subjects.Vital sign recheck was not performed at the 2.25-hour time point ofPeriod 3 for one subject. The blood samples for these two subjects werenot labeled properly at the 0.33-hour time point of Period 1 (TreatmentA). These samples were not analyzed. According to the protocol, subjectswere to have pulse taken at the 3.5-hour vital signs time point. Pulsewas not taken at the 3.5-hour time point for one subject duringPeriod 1. No one subject was exposed to more than one of the foregoingdeviations. No serious adverse events were reported.

A total of 15 batches were required to process the clinical samples fromthis study. Of these 15 batches, 14 were acceptable. Back-calculatedstandard concentrations for the 14 acceptable batches for human serumused in this study covered a range of 50.0 to 5000.0 pg/mL(picograms/mL) with a limit of quantitation of 50.0 pg/mL. Qualitycontrol samples analyzed with each acceptable batch had coefficients ofvariation less than or equal to 7.89%.

Dwell Time

The dwell time data are summarized in the table below. Summary ofTablet/Lozenge Dwell Time Treatment Treatment Treatment Treatment A BTreatment C D E Subject Time Time Time Time Time Number (Minutes)(Minutes) (Minutes) (Minutes) (Minutes Mean 21 34 19 25 22 SD 12 15 1114 17 CV 58 44 56 57 75 SEM 2 2 3 4 4 N 40 42 12 13 14 Minimum 3 9 4 4 4Maximum 48 77 33 50 62Treatment A = 1 × 1080 mcg OraVescent Fentanyl Citrate Tablet: testTreatment B = 1 × 1600 mcg Oral Transmucosal Fentanyl Citrate (Actiq):referenceTreatment C = 1 × 1300 mcg OraVescent Fentanyl Citrate Tablet: testTreatment D = 1 × 810 mcg OraVescent Fentanyl Citrate Tablet: testTreatment E = 1 × 270 mcg OraVescent Fentanyl Citrate Tablet: testSD = standard deviation;CV = coefficient of variance;SEM = standard error of the mean;N = number (of observations)

One subject reported slight oral irritation (2 on a scale of 1 to 10)that occurred following Treatment C. The irritation was on the rightside of the mouth following test product administration during Period 3.There was one report of redness upon visual inspection of the area bystudy personnel that occurred following Treatment E. The redness was onthe right upper cheek following test product administration duringPeriod 3.

Of the 42 subjects enrolled, 40 subjects completed Periods 1 and 2 andwere included in the summary statistics, ANOVA analysis, and meanfigures for Treatments A and B. Thirty-nine subjects completed Periods1, 2, and 3 and were included in the statistical analysis for doseproportionality.

The arithmetic means and standard deviations of the serum fentanylpharmacokinetic parameters and statistical comparisons followingTreatment A and Treatment B are summarized in the following table.Summary of the Pharmacokinetic Parameters of Serum Fentanyl forTreatments A and B Serum Fentanyl Treatment A Treatment BPharmacokinetic Arithmetic Arithmetic % Mean Parameters N Mean SD N MeanSD 90% CI* Ratio Cmax (pg/mL) 40 2704.3 877.6 40 2191.6 693.5 —-— —AUC(0-tmax) (pg * hr/mL) 40 3840.1 1266.2 40 2566.2 911.82 —-— —AUC(0-t) (pg * hr/mL) 40 16537 5464.6 40 16701 6530.1 —-— — AUC(0-inf)(pg * hr/mL) 35 17736 5424.3 39 18319 7118.5 —-— — T½(hr) 35 11.7 5.0439 11.2 4.37 —-— — Kel(1/hr) 35 0.0701 0.0310 39 0.0695 0.0227 —-— —AUCR 35 0.918 0.0458 39 0.917 0.0335 —-— — ln(Cmax) 40 7.854 0.3132 407.640 0.3349 111.82-136.20 123.4 ln[AUC(0-t)] 40 9.662 0.3226 40 9.6490.3945  94.42-108.86 101.4 ln[AUC(0-inf)] 35 9.739 0.3027 39 9.7420.3941  93.60-109.23 101.1*= Based on LS Means from Table 13.Treatment A = 1 × 1080 mcg OraVescent Fentanyl Citrate Tablet: testTreatment B = 1 × 1600 mcg oral Transmucosal Fentanyl Citrate (Actiq):reference

Results of the Wilcoxon Signed Rank Test showed the median Tmax forTreatment A (0.998 hour) was significantly earlier (p<0.0001) comparedto Treatment B (1.999 hours).

The individual and mean serum fentanyl pharmacokinetic parameters forTreatments C, D, and E were calculated. There were 5 subjects inTreatment E for whom Kel could not be calculated. Thus, AUC(0-inf),AUCR, and T½ could not be calculated in these cases.

The arithmetic mean and standard deviations of the serum fentanylpharmacokinetic parameters following Treatments C, D, and E aresummarized in the following table. Summary of the PharmacokineticParameters of Serum Fentanyl for Treatments C, D, and E Serum FentanylTreatment C Treatment D Treatment E Pharmacokinetic ArithmeticArithmetic Arithmetic Parameters N Mean SD N Mean SD N Mean SDCmax(pg/mL) 12 2791.4 874.3 13 2646.9 778.7 14 797.9 312.9 AUC(0-tmax)(pg * hr/mL) 12 4008.3 1259.1 13 3694.8 971.89 14 1095.6 433.92 AUC(0-t)(pg * hr/mL) 12 18921 6470.2 13 15339 4260.4 14 4333.5 1597.9 AUC(0-inf)(pg * hr/mL) 12 21033 7346.3 13 16831 4449.8 9 4221.9 1747.8 T½(Hr) 1213.2 7.67 13 11.7 4.66 9 6.62 3.17 Kel(1/hr) 12 0.0687 0.0354 13 0.07030.0352 9 0.126 0.0538 AUCR 12 0.907 0.0683 13 0.909 0.0376 9 0.8650.0381Treatment C = 1 × 1300 mcg OraVescent Fentanyl Citrate TabletTreatment D = 1 × 810 mcg OraVescent Fentanyl Citrate TabletTreatment E = 1 × 270 mcg OraVescent Fentanyl Citrate TabletAUCR is ratio of AUC_(0-t)/AUC_(0-∞)

The dose proportionality assessment including p-values for Treatments A,C, D, and E are summarized in the following table. Summary of theDose-Normalized Parameters of Serum Fentanyl for Treatments A, C, D andE Serum Fentanyl Treatment A Treatment C Treatment D Treatment EPharmacokinetic Arithmetic Arithmetic Arithmetic Arithmetic ParametersP-Value Mean SD Mean SD Mean SD Mean SD Cmax/dose — 2.5 0.8 2.1 0.7 3.31.0 3.0 1.2 (pg/mL/mcg) AUC(0-t)/dose — 15.4743 5.01901 14.555 4.977118.937 5.2597 16.050 5.9180 (pg * hr/mL/mcg) AUC(0-inf)/dose — 16.58515.00318 16.179 5.6510 20.779 5.4935 15.637 6.4732 (pg * hr/mL/mcgln(Cmax/dose) 0.0127 0.8788 0.3115 0.7190 0.3151 1.137 0.3356 1.0110.3974 Ln[AUC(0-t)/dose] 0.1727 2.690 0.3170 2.625 0.3409 2.901 0.30322.706 0.4002 ln[AUC(0-inf)/ 0.0783 2.765 0.3003 2.725 0.3633 2.9980.2894 2.691 0.3892 dose]Treatment A = 1 × 1080 mcg OraVescent Fentanyl Citrate TabletTreatment C = 1 × 1300 mcg OraVescent Fentanyl Citrate TabletTreatment D = 1 × 810 mcg OraVescent Fentanyl Citrate TabletTreatment E = 1 × 270 mcg OraVescent Fentanyl Citrate TabletThe time intervals over Kel values were determined.

The primary objective of this study was to assess the bioequivalence ofa 1080 μg dose of CIMA LABS INC OraVescent® Fentanyl Citrate tablet(Treatment A, test) compared to a marketed 1600 μg oral transmucosalfentanyl citrate, Actiq® (Treatment B, reference) under fastedconditions. The study was a single-dose randomized, open-label, 2-waycrossover design for Periods 1 and 2. All subjects also returned inPeriod 3 for administration of one of three OraVescent® Fentanyl Citratetest formulations: 1300 μg (Treatment C), 810 μg (Treatment D), or 270μg (Treatment E). Dose-proportionality of the OraVescent® FentanylCitrate tablet formulation (Treatments A, C, D, and E) was evaluated.

A total of 42 healthy subjects were initially enrolled in the study. 39subjects completed all three periods of the study, and 40 subjectscompleted both Treatments A and B (Periods 1 and 2). Data from the 40subjects completing Treatments A and B were included in thepharmacokinetic and statistical analysis.

The ratios of geometric least square means (test/reference) for fentanylCmax, AUC(0-t), and AUC(0-inf) were 123.4%, 101.4%, and 101.1%,respectively, for Treatment A versus Treatment B. These data indicatethat the average fentanyl exposure was similar but the peak exposure washigher for Treatment A compared to Treatment B. The Tmax for Treatment A(0.998 hour) occurred an hour earlier than Treatment B (2.00 hour) andCmax was 23% higher, indicating that the rate of fentanyl absorption wassignificantly faster for Treatment A compared to Treatment B.

The 90% confidence intervals for Cmax at 111.82%-1.36.20%, AUC(0-t) at94.42%-108.86%, and AUC(0-inf) at 93.60%-109.23% indicated thatTreatment A and Treatment B met the requirements for bioequivalence withrespect to AUC but not with respect to Cmax. In fact, the Cmax ofTreatment A indicates that a dose of about 30-35% less fentanyl byweight given using the OraVescent® formulation exemplified in Example 1provided a statistically significantly higher Cmax when compared to a1600 microgram Actiq® formulation. To obtain bioequivalent results interms of Cmax, indeed to obtain comparable results, one would have touse an OraVescent® fentanyl formulation including at least about 45%,more preferably about 47.5% and even more preferably about 50% lessfentanyl (calculated as free fentanyl by weight) than found in thecomparator Actiq® tablet. In this instance, approximately 800-880micrograms was compared to a 1600 microgram ACTIQ.

Thus it was discovered that, using the present invention and for dosageforms of 1 milligram or less, one could obtain comparable C_(max) witheven less fentanyl than initially thought. Rapid T_(max) was realized.This allowed a further reduction in the doses contemplated with theadvantages described herein that come from a dose reduction that is notcoupled with a reduction in efficacy.

Fentanyl AUC increased proportionally (linearly as defined herein) tothe dose in the range of 270 to 1300 μg following administration of theOraVescent® Fentanyl Citrate tablet formulation. There were nosignificant differences in dose-normalized AUC(0-t) or AUC(0-inf) amongthe 4 OraVescent® doses. A significant overall treatment effect wasfound for the comparison of dose-normalized Cmax. Pairwise comparisonswere performed using Treatment A as the reference because all subjectsreceived Treatment A. No pattern was observed with the pairwisecomparisons. A significant difference between Treatment D (810 μg) andTreatment A (1080 μg) was found.

The mean dwell time of the 1080 μg OraVescent® Fentanyl Citrate tablet(21 minutes) was 13 minutes shorter than for Actiq® (34 minutes). Meandwell times for the other 3 doses of the OraVescent® Fentanyl Citratetablet formulation (19, 25, and 22 minutes) were similar to 1080 μgOraVescent® formulation.

One subject reported minor irritation to the oral mucosa, and onesubject experienced redness following the OraVescent® Fentanyl Citratetablet. There was no irritation or redness reported following Actiq®.

Comparison of serum fentanyl pharmacokinetics following theadministration of 1080 μg OraVescent® Fentanyl Citrate tablet and 1600μg oral transmucosal fentanyl citrate (Actiq®) showed that the averagefentanyl exposure was similar but the rate of absorption was differentbetween the two products. The geometric least square (“LS”) mean ratiosfor AUC(0-t) and AUC(0-inf) were near 100%, and 90% confidence intervalswere within 80% to 125%. Geometric mean Cmax was 23% higher for 1080 μgOraVescent® Fentanyl Citrate, and the upper limit of the 90% confidenceinterval for the treatment/reference ratio was greater than 125%,indicating that bioequivalence criteria were not met for this parameter.Thus even further dose reduction could be realized. The Tmax wassignificantly earlier (1 hour earlier) for the OraVescent® FentanylCitrate tablet.

Fentanyl AUC increased proportionally to the dose, but not completelylinearly over the whole dose range in the range of 270 to 1300 μg forthe OraVescent® Fentanyl Citrate formulation.

The mean dwell time for the 1080 μg OraVescent® Fentanyl Citrate tablet(21 minutes) was 13 minutes shorter than the mean dwell time for Actiq®(34 minutes). “Dwell time” in accordance with the invention is theamount of time between beginning of use of dosage form (insertion intothe mouth) and disappearance of all visually identifiable dosage form.

There were no serious or unexpected adverse events during the study.Both formulations were well tolerated by the oral mucosa.

References

-   1. Physician's Desk Reference. 56th ed. Montvale, N.J.: Medical    Economics Company, Inc.; 2002. Actiq®; p. 405-409.-   2. Fentanyl. Micromedex [online] Vol. 107: Health Series Integrated    Index; 2002 [Date Accessed: 2003/June/371. http://www.tomescps.com-   3. Streisand Y B, et al. Dose Proportionality and Pharmacokinetics    of Oral Transmucosal Fentanyl Citrate. Anesthesiology 88:305-309,    1998.-   4. Naltrexone. Micromedex [online] Vol. 107: Health Series    Integrated Index; 2002 [Date Accessed: 2003/June/I6].    http://www.tomescps.com-   5. SAS Institute, Inc., SAS®/STAT User's guide, Ver. 6. 4th ed.    Vol. 1. Cary, N.C.: SAS Institute; 1989.-   6. SAS Institute, Inc., SAS®/STAT User's guide, Ver. 6, 4th ed.    Vol. 2. Cary, N.C.: SAS Institute; 1989.-   7. SAS Institute, Inc., SAS® Procedures guide, Ver. 6, 3rd ed. Cary,    N.C.: SAS Institute; 1990.

A second study was performed as well. This study demonstrated agenerally linear relationship between dose and C_(max) over the doserange of 100-800 micrograms.

This study was conducted to evaluate the dose proportionality (AUC andCmax) of fentanyl citrate formulated in tablets in accordance with theinvention (referred to herein as OraVescent® tablets) over the rangethat may be used therapeutically, and to confirm the Cmax observationsof the study just discussed.

An Institutional Review Board (IRB) approved the protocol and theInformed Consent Form. All subjects read and signed an IRB-approved ICFprior to study initiation. This study had a single-dose, randomized,open-label, 4-treatment, 4-period, crossover design.

The subjects were screened within 21 days prior to study enrollment. Thescreening procedure included medical history, physical examination(height, weight, frame size, vital signs, and electrocardiogram [ECG]),and clinical laboratory tests (hematology, serum chemistry, urinalysis,HIV antibody screen, hepatitis A antibody screen, hepatitis B surfaceantigen screen, hepatitis C antibody screen, and serum pregnancy[females only]), and a screen for cannabinoids and opiates.

All subjects enrolled in the study satisfied the inclusion/exclusioncriteria as listed in the protocol and the Principal Investigatorreviewed medical histories, clinical laboratory evaluations, andperformed physical examinations prior to subjects being enrolled in thestudy. A total of 28 subjects, 16 males and 12 females, were enrolled inthe study, and 25 subjects, 14 males and 11 females, completed thestudy.

Subjects reported to the clinic on the afternoon prior to dosing andreceived lunch at 1400, dinner at 1900, and a snack at 2200. Thesubjects then observed a 10-hour overnight fast. On Day 1, astandardized meal schedule was initiated with lunch at 1330, dinner at1830, and a snack at 2200. On Day 2, a standardized meal schedule(including breakfast) was initiated.

The subjects were not to consume any alcohol, broccoli, caffeine-, orxanthine-containing foods or beverages for 48 hours prior to and duringeach period of confinement. Grapefruit was restricted 10 days prior todosing and throughout the study. Subjects were to be nicotine- andtobacco-free for at least 6 months prior to and throughout thecompletion of the study. In addition, over-the-counter medications(including herbal supplements) were prohibited 7 days prior to dosingand during the study. Prescription medications (including MAOinhibitors) were not allowed 14 days prior to dosing and during thestudy.

During the study, subjects were to remain in an upright position,sitting, for 4 hours after the fentanyl citrate was administered. Waterwas restricted from the time of dosing until 4 hours postdose. Food wasrestricted 10 hours predose until 4 hours postdose. During the study,the subjects were not allowed to engage in any strenuous activity.

Subjects were randomized to receive the following treatments:

-   -   Adml: ReVia® (naltrexone hydrochloride tablets) 50 mg        Manufactured by Duramed Pharmaceuticals, Inc.    -   Lot No.: 402753001T    -   Expiration date: June 2006

Subjects received an oral dose of one ReVia® 50 mg tablet taken with 240mL of water 15 hours and 3 hours prior to dosing for Treatment A.

Subjects received an oral dose of one ReVia® 50 mg tablet taken with 240mL of water 15 hours and 3 hours prior to dosing, and 12.17 hourspostdose for Treatment B, C, and D.

-   -   A: Oravescent® Fentanyl Citrate 200 μg tablets Manufactured by        CIMA LABS INC        -   Lot No.: 930859

Subjects randomized to Treatment A received a single oral dose of oneOravescent® Fentanyl Citrate 200 μg tablet placed between the upper gumand cheek, above a molar tooth, and allowed to disintegrate for 10minutes.

-   -   B: Oravescent® Fentanyl Citrate 500 μg tablets Manufactured by        CIMA LABS INC        -   Lot No.: 930860

Subjects randomized to Treatment B received a single oral dose of oneOravescent® Fentanyl Citrate 500 μg tablet placed between the upper gumand cheek, above a molar tooth, and allowed to disintegrate for 10minutes.

-   -   C: Oravescent® Fentanyl Citrate 810 μg tablets Manufactured by        CIMA LABS INC        -   Lot No.: 930501

Subjects randomized to Treatment C received a single oral dose of oneOravescent® Fentanyl Citrate 810 jig tablet placed between the upper gumand cheek, above a molar tooth, and allowed to disintegrate for 10minutes.

-   -   D: Oravescent® Fentanyl Citrate 1080 μg tablets Manufactured by        CIMA LABS INC        -   Lot No.: 930502

Subjects randomized to Treatment D received a single oral dose of oneOravescent® Fentanyl Citrate 1080 jig tablet placed between the uppergum and cheek, above a molar tooth, and allowed to disintegrate for 10minutes.

Sitting vital signs (blood pressure, heart rate, and respiratory rate)were assessed each morning prior to dosing and at 0.25, 0.5, 0.75, 1,1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 10,24, and 36 hours postdose. Continuous pulse oximetry was obtained forthe first 8 hours postdose and whenever the subject attempted to sleepduring the first 12 hours postdose. A 12-lead ECG, a clinical laboratoryevaluation (hematology, serum chemistry, and urinalysis) and a briefphysical examination with complete vital signs were performed at thecompletion of the study. Oral irritation assessments were conducted 4hours postdose. At each check-in, the oral cavity was examined to ensurethat the subjects did not have canker sores in the area of drugapplication. Subjects were instructed to inform the study physician ornurses of any adverse events that occurred during the study.

Blood samples (7 mL) were collected at the following times for subjectsassigned to Treatment A: Predose (Hour 0), 10, 20, 30, and 45 minutes;and 1, 2, 4, 6, 8, 9, 10, 11, 12, 14, 16, 20, and 24 hours postdose.Blood samples (7 mL) were collected at the following times for subjectsassigned to Treatments B, C and D: Predose (Hour 0), 10, 20, 30, and 45minutes; and 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, and 36 hourspostdose.

Human serum samples were analyzed for fentanyl concentrations by asensitive and specific LC-MS/MS procedure.

The following noncompartmental pharmacokinetic parameters were computedfrom the fentanyl concentration-time data for each treatment usingWinNonlin Standard Edition version 2.1. Actual (rather than nominal)sampling times were used in the analysis.

-   -   AUC(0-t) Area under the fentanyl concentration-time curve        calculated using linear trapezoidal summation from time zero to        time t, where t is the time of the last measurable concentration        (Ct).    -   AUC(0-inf) Area under the fentanyl concentration-time curve from        time zero to infinity, AUC(0-inf)=AUC(0-t)±Ct/Kel, where Kel is        the terminal elimination rate constant.    -   AUC(0-t)/AUC(0-inf) Ratio of AUC(0-t) to AUC(0-inf). Also        referred to as AUCR. Kel Terminal elimination rate constant        calculated by linear regression of the terminal linear portion        of the log concentration vs. time curve, where Kel=−slope. The        terminal linear portion was determined by visual inspection.    -   T½ Elimination half-life calculated as ln(2)/Kel.    -   Cmax Maximum observed fentanyl concentration.    -   Tmax Time of the maximum fentanyl concentration (obtained        without interpolation).

Plasma concentration values for fentanyl were listed and summarized bytreatment and time point with descriptive statistics (mean, standarddeviation [SD], coefficient of variation [CV], standard error of themean [SEM], sample size, minimum, maximum, and median).⁹⁻¹¹ Values belowthe lower limit of quantification (LOQ) were set to zero. Mean andindividual concentration-time plots were presented. Fentanylpharmacokinetic parameters and dose-normalized pharmacokineticparameters were tabulated by treatment and summary statistics werecalculated.

Dose proportionality from 200 μg to 1080 μg was assessed using themethodology described by Smith et al.⁸ First, log-transformed parameterswere analyzed using a mixed effects model including thelog-transformation of dose as well as fixed and random effects forintercept. This model was fit using SAS Proc Mixed.⁹⁻¹¹

A 90% confidence interval (CI) about the fixed effect for slope (β₁) wascalculated and compared to the range (0.8677, 1.1323), which is theappropriate critical range given the range of doses investigated in thisstudy. Conclusions were based on the following:

-   -   1) If the 90% CI for β₁ was entirely contained within the range        (0.8677, 1.1323), dose proportionality was to be concluded.    -   2) If the 90% CI for β₁ was completely outside this range, lack        of dose proportionality was to be concluded.    -   3) If the 90% CI for β₁ was partially in and partially outside        this range, the results would be considered “inconclusive.” In        this case, the value of β₁ as the best estimate of deviation        from ideal proportionality, and the lower and upper bounds of        the 90% CI may be considered in the context of drug safety,        efficacy, or pharmacological effect data.⁸

In the event that inconclusive results were observed, the maximal doseratio such that the 90% CI for β₁ lay entirely within the critical rangeand the dose ratio such that the 90% CI for β₁ fell entirely outside thecritical range were calculated. These dose ratios are referred to bySmith et al., as ρ1 and ρ2, respectively.

-   ρ₁=θ_(H{circumflex over ( )})[1/max(1−L, U−1)], where θ_(H)=1.25,-   L=the lower limit of the 90% CI,-   U=the upper limit of the 90% CI.-   ρ₂=θ_(H{circumflex over ( )})[1/max(L−1, 1−U)], with θ_(H), L, and U    and defined as above.

A secondary analysis to examine the difference in dose-normalized Cmaxbetween the 3 lowest dose levels (200 μg, 500 μg, and 810 μg) wasperformed. A parametric (normal-theory) GLM was applied to thedose-normalized Cmax values from Treatments A, B, and C followinglog-transformation. The analysis of variance (ANOVA) model included thefollowing factors: treatment, sequence, subject within sequence andperiod. A p-value less than 0.05 was considered statisticallysignificant.

The dwell time values (length of time the formulation was present in theoral cavity) were calculated by subtracting the medicationadministration time from the time of perceived and documenteddisappearance of the formulation. These values were tabulated andsummary statistics were presented.

Three subjects were discontinued/withdrawn from the study. Two weredropped prior to Period 3 because they did not want to continue on thestudy. One subject was dropped following dosing on Period 2 because ofadverse events. The mean age of the subjects was 33 years (range 19-55years), the mean height of the subjects was 68.6 inches (range 60-76inches), and the mean weight of the subjects was 160.9 pounds (range110-215 pounds).

The following protocol deviations occurred during the conduct of thestudy. A vital sign recheck was not performed at Hour 0.5 of Period 2for one subject. A vital sign recheck was not performed at Hour 2.5 ofPeriod 3 for one subject. One subject did not have her serum pregnancytest result available prior to the −15-hour naltrexone dosing on Period3. The result was made available prior to the 31 3-hour naltrexone dose.The ECG for Hour 36 of Period 4 was misplaced for one subject. Onesubject did not have early termination procedures completed. Thissubject is considered lost to follow-up. And, for all subjects duringPeriod 3, an oral irritation assessment was to have been conducted at3.83 hours postdose. The nurse responsible for the event recalledperforming the assessments but stated that the oral irritationassessment forms were not completed at the time of the event. Therefore,the assessment information cannot be verified and should be considerednot done.

The dwell time data are summarized in the table below. Treatment ATreatment B Treatment C Treatment D Subject Time Time Time Time Number(Minutes) (Minutes) (Minutes) (Minutes) MEAN 14 14 17 15 SD 8 6 10 11 CV59 45 57 72 SEM 2 1 2 2 N 25 26 27 27 Minimum 4 6 5 4 Maximum 37 33 4160Treatment A = 200 μgTreatment B = 500 μgTreatment C = 810 μgTreatment D = 1080 μg

During the check-in oral cavity assessments it was noted that onesubject had a canker sore on the lower right inner cheek at thebeginning of Period 4, however, the test product administration duringPeriod 3 occurred on the upper right cheek. The Principal Investigatoridentified this canker sore as not an apthous ulcer and approved thesubject to dose during Period 4.

Two subjects reported slight oral irritation (2 and 3 on a scale of 1 to10) that occurred following Treatment A. The irritation was on the leftside of the mouth following test product administration during Period 2for both subjects; one of these subjects also exhibited redness uponvisual inspection of the area by study personnel. One additional subjectreported pain in the upper left buccal area at the gum line 11 minutesfollowing Treatment C. No serious or unexpected adverse events werereported.

Of the 28 subjects enrolled, 25 subjects completed Treatment A, 26subjects completed Treatment B, and 27 subjects completed Treatments Cand D. Statistical analysis was performed on the pharmacokinetic datafor all subjects. The elimination rate constant could not be calculatedin one subject in Treatment A because there were limited data points inthe terminal phase. Thus, AUC(0-inf), AUCR, and T½ could not becalculated for this subject.

The arithmetic means and standard deviations of the serum fentanylpharmacokinetic parameters following all treatments are summarized inthe following table. Summary of the Phamacokinetic Parameters of SerumFentanyl SERUM FENTANYL Treatment A Treatment B Treatment C Treatment DPharmacokinetic Arithmetic Arithmetic Arithmetic Arithmetic Parameters NMean SD N Mean SD N Mean SD N Mean SD C_(max) (pg/mL) 25 617.8 236.7 261546.2 621.4 27 2280.1 968.9 27 2682.3 1106.0 *T_(max) (hr) 25 0.760.33-4.0 26 0.75 0.33-4.0 27 0.99 0.33-4.0 27 0.75 0.33-4.0 AUC(0-t)(pg * hr/mL) 25 2876.3 1107.7 26 8501.2 3346.2 27 13301 4069.1 27 168135232.2 AUC(0-inf) (pg * hr/mL) 24 3543.9 1304.5 26 9701.9 2651.5 2714962 4709.6 27 18664 6266.0 T½(hr) 24 6.48 3.69 26 12.0 8.18 27 12.84.08 27 11.4 4.34 Kel (1/hr) 24 0.143 0.0802 26 0.0746 0.0377 27 0.05920.0167 27 0.0679 0.0216 AUCR 24 0.843 0.0604 26 0.875 0.0929 27 0.8930.0589 27 0.909 0.0602 C_(max)/dose (pg/mL/mcg) 25 3.09 1.18 26 3.091.24 27 2.81 1.20 27 2.48 1.02 AUC(0-t) (pg * hr/mL/mcg) 25 14.4 5.54 2617.0 6.69 27 16.4 5.02 27 15.6 4.84 AUC(0-inf) (pg * hr/mL/mcg) 24 17.76.52 26 19.4 7.30 27 18.5 5.81 27 17.3 5.80 ln(C_(max)/dose) 25 1.060.383 26 1.05 0.426 27 0.945 0.439 27 0.836 0.386 ln[AUC(0-t)/dose] 252.59 0.424 26 2.75 0.441 27 2.75 0.324 27 2.69 0.356 ln[AUC(0-int)/dose]24 2.81 0.369 26 2.89 0.413 27 2.87 0.329 27 2.79 0.372*Median and min-max are reported for Tmax.Treatment A = 1 × 200 mcg OraVescent Fentanyl Citrate TabletTreatment B = 1 × 500 mcg OraVescent Fentanyl Citrate TabletTreatment C = 1 × 810 mcg OraVescent Fentanyl Citrate TabletTreatment D = 1 × 1080 mcg OraVescent Fentanyl Citrate Tablet

The slopes of ln [AUC(0-t)] versus ln(dose) and ln [AUC(0-inf)I versusln(dose), at 1.0574 and 0.9983, respectively, 1, and the 90% CI for eachparameter was completely contained within the critical range requiredfor dose proportionality from 200 μg to 1080 μg. The slope of ln(Cmax)versus ln(dose), 0.8746, was less than 1 and the 90% CI (0.8145-0.9347)was not completely contained within the critical range required for theconclusion of dose proportionality. The maximal dose ratio such that the90% CI for β₁ lay entirely within the critical range was 3.33. Themaximal dose ratio such that the 90% CI for β₁ fell entirely outside thecritical range was 30.48. The results of the ANOVA of dose-normalizedC_(max) for Treatments A, B, and C indicate that there was nostatistically significant difference in dose-normalized Cmax in the doserange of 200 μg to 810 μg (p=0.13).

The primary objective of this study was to evaluate the extent to whichdose proportionality exists for fentanyl AUC and Cmax following fentanyldoses of 200 μg (Treatment A), 500 μg (Treatment B), 810 μg (TreatmentC), and 1080 μg (Treatment D) as OraVescent® Fentanyl Citrate tablets.In addition, this study was conducted to confirm previous observationsrelating to Cmax following the administration of 810 μg and 1080 μgdoses of OraVescent® Fentanyl Citrate tablets. This study was asingle-dose, randomized, open-label, 4-period crossover design.

Of the 28 subjects enrolled, 25 subjects completed Treatment A, 26subjects completed Treatment B, and 27 subjects completed Treatments Cand D. Statistical analysis was performed on the pharmacokinetic datafor all subjects.

The slopes of ln [AUC(0-t)] versus ln(dose) and ln [AUC(0-inf)] versusln(dose), at 1.0574 and 0.9983, respectively, were close to 1, and the90% CI for each parameter was completely contained within the criticalrange required for dose proportionality. These results indicate thatfentanyl AUC increased proportionally with each increasing dose level ofOraVescent® Fentanyl Citrate tablets between the study doses of 200 μgto 1080 μg.

The slope of ln(Cmax) versus ln(dose), 0.8746, was less than 1,indicating that fentanyl Cmax increased less than proportionally todose. The 90% CI (0.8145-0.9347) was not entirely contained within thecritical range. The less than proportional increase was observed at thehighest dose (1080 μg) and, to a lesser extent (±11% confidenceinterval), at the second to highest dose (810 μg). Cmax increasedproportionally from 200 μg to 500 μg. The value for ρ₁ (maximal doseratio such that the 90% CI for β₁ lay entirely within the criticalrange) was 3.33, whereas the ratio of 810 μg:200 μg is 4.05. Thisindicates that the formulation is linear in accordance with theinvention, up to about 800 micrograms in dose.

A secondary analysis using ANOVA to compare dose-normalized Cmax fromthe 200 μg, 500 μg, and 810 μg doses indicated no statisticallysignificant difference (p=0.13) between these dose levels. The LS meansfor ln(Cmax/dose) were 1.06 (200 μg), 1.06 (500 μg), and 0.94 (810 μg),showing no difference between the 200 and 500 μg doses and a minimal(less than 15%) difference in the 810 μg dose compared to the lowerdoses. The lack of significant differences from the ANOVA in conjunctionwith the small magnitude in the difference between the 810 μg dose andthe 2 lower doses indicates that there is not a clinically importantdeviation in dose proportionality in Cmax from 200 μg to 810 μg. Thus,they are “linear” as defined herein.

The mean dwell time for the 200 μg, 500 μg, 810 μg, and 1080 μgOraVescent® Fentanyl Citrate tablets were similar, at 14 minutes, 14minutes, 17 minutes, and 15 minutes, respectively.

There were 2 subjects who reported minor irritation to the oral mucosaand 1 subject who experienced redness following the OraVescent® FentanylCitrate tablet.

Fentanyl AUC increased proportionally with increasing dose in the rangeof 200 μg to 1080 μg. Fentanyl Cmax increased less than proportionallyto dose at the two highest dose levels. The increase was, however,linear as defined herein in all but the dose greater than 1 milligram.Mean ln(Cmax/dose) for the 810 μg dose was 10 to 11% lower than the 200μg and 500 μg doses. Mean ln(Cmax/dose) for the 1080 μg dose was 20 to21% lower than the 200 μg and 500 μg. There was not a clinicallyimportant deviation in dose proportionality in Cmax from 200 μg to 810μg. The mean dwell time for the 200 μg, 500 μg, 810 μg, and 1080 μgOraVescent® Fentanyl Citrate tablets were similar, at 14 minutes, 14minutes, 17 minutes, and 15 minutes, respectively.

There were no serious or unexpected adverse events during the study.Each OraVescent® formulation was well tolerated by the oral mucosa.

References

-   8. Smith B P, et al. Confidence Interval Criteria for Assessment of    Dose Proportionality. Pharmaceutical Research 17:1278-1283, 2000.-   9. SAS Institute, Inc., SAS®/STAT User's guide, Ver. 6. 4th ed.    Vol. 1. Cary, N.C.: SAS Institute; 1989.-   10. SAS Institute, Inc., SAS®/STAT Users guide, Ver. 6, 4th ed.    Vol. 2. Cary, N.C.: SAS Institute; 1989.-   11. SAS Institute, Inc., SAS® Procedures guide, Ver. 6, 3rd ed.    Cary, N.C.: SAS Institute; 1990.-   12. Summary Basis of Approval NDA 20-747 (Actiq®). Approval date    Nov. 4, 1998, Clinical Pharmacology and Biopharmaceutics Review pp    6.

Any formulation which contains sufficient effervescent material and pHadjusting substance, preferably with a suitable disintegrant, which iscapable of providing a dosage form useful in buccal, gingival, orsublingual administration of fentanyl at dose levels which arecontemplated herein and providing for the dose reductions and/or dose toCmax relationships disclosed herein may be used. Most preferably, fordosage forms containing about 100-800 micrograms of fentanyl (calculatedas free base) any effervescent couple and/or pH adjusting substancewhich can be provided in an amount that produces a dosage form having aT_(max) of 1.5 hours or less and/or provides a C_(max) to dose ofbetween about 2.0 and about 4.0 picograms/mL/micrograms, more preferablybetween about 2.5 and about 3.5, and even more preferably between about2.7 and about 3.5 picograms/mL/micrograms may be used. Preferably, thedosage forms will also exhibit a linear relationship between C_(max) anddose as described herein. This means that the Cmax to dose ratio willfall along the line (p≦0.15) generated by a series of at least threedifferent doses between 100 and 800 micrograms of fentanyl of theinvention having the same composition but for the amount of fentanyl.

Similarly, any amount of effervescent couple and pH adjusting substancewhich provides a dosage form having comparable C_(max) when compared toan ACTIQ formulation having at least about 80% more fentanyl iscontemplated. That is it has a C_(max) of at least 75% to 125% of theC_(max) of such an ACTIQ formulation, more preferably between about 80%and about 125% (p less than or equal to 0.15) and most preferablybetween about 85% and about 115% of an ACTIQ formulation, despite havingat least 45% less fentanyl (calculated as a freebase). In a particularlypreferred embodiment, these formulations will not include a significantamount of any disintegrant or excipient or combination of excipientswhich will interfere with such performance characteristics. Spray driedmannitol is a preferred filler. Another preferred excipient is adistintegrant which is starch glycolate and in particular sodium starchglycolate. The former is typically characterized as a filler and thelatter a disintegrant. However, such characterizations are notcontrolling.

Formulations in the '604 patent which included lactose monohydrate in anamount of greater than 20% and/or microcrystalline cellulose in anamount of at least about 20% and cross-linked PVP in an amount of 5% ormore are believed to be unable to provide formulations having thedesirable linear behavior of dose and C_(max) of the levels discussedherein, despite the presence of a pH adjusting substance and aneffervescent couple. The formulations in the '604 patent also have morethan 880 μg of fentanyl.

A preferred effervescent, orally disintegrable dosage form in accordancewith the present invention is one that includes, based on the weight ofthe free base material, between about 100 and 800 micrograms of fentanyl(90 to 880), or a proportionate weight of one of its pharmaceuticallyacceptable salts. In addition, these numbers are meant to include normalprocessing variabilities such as content uniformity, etc. Particularlypreferred doses are about 100 micrograms, about 200 micrograms, about300 micrograms, about 400 micrograms, about 600 micrograms and about 800micrograms, respectively.

It is preferred that the mean particle size as determined by a laserdiffraction technique of fentanyl used in the present formulation rangefrom between about 0.2 to about 150 microns, more preferably frombetween about 0.5 to about 100 and most preferably from between about 1to about 20 microns.

As an effervescent agent or effervescent couple, any known combinationmay be used. These include those described in U.S. Pat. Nos. 5,178,878and 5,503,846, the texts of which are hereby incorporated by referenceto the extent they discuss various effervescent couples andconstructions of same. Effervescent couples generally are water- orsaliva-activated materials usually kept in an anhydrous state withlittle or no absorbed moisture or in a stable hydrated form. Typicallythese involve at least one acid source and at least one source of areactive base, usually a carbonate or bicarbonate. Each of thecomponents of the effervescent couple may be any which are safe forhuman consumption.

The acids generally include food acids, acid anhydrides and acid salts.Food acids include citric acid, tartaric acid, malic acid, fumeric acid,adipic acid, ascorbic acid and succinic acid. Acid anhydrides or saltsof these acids may be used. Salts in this context may include any knownsalt but in particular, sodium, dihydrogen phosphate, disodiumdihydrogen phosphate, acid citrate salts and sodium acid sulfate. Basesuseful in accordance with the invention typically include sodiumbicarbonate, potassium bicarbonate and the like. Sodium carbonate,potassium carbonate, magnesium carbonate and the like may also be usedto the extent they are used as part of an effervescent couple. However,they are more preferably used as a pH adjusting substance. Preferably,stoichiometric equivalent amounts of acid, acid anhydride or acid saltand base are used. It is possible, however, that some excess of acid orbase be used. However, care should be exercised when so formulating aformulation, particularly in view of the overall pH adjusting effect ofsuch components, if any. An excess could affect absorption.

The amount of effervescent material useful in accordance with thepresent invention is an effective amount and is determined based onproperties other than those which would be necessary to achievedisintegration of the tablet in the mouth. Instead, effervescence isused as a basis for enhancing transmission of the fentanyl acrossmucosal membranes via buccal, gingival or sublingual administration inthe oral cavity. Accordingly, the amount of effervescent couple shouldrange from between about 5 to about 85 percent, more preferably betweenabout 15 to 60 percent, even more preferably between about 30 and 45percent and most preferably between about 35 to about 40 percent, basedon the weight of the total formulation. Of course, the relativeproportion of acid base will depend upon the specific ingredients (forexample, whether the acid monoprotic, diprotic or triprotic) relativemolecular weights, etc. However, preferably, a stoichiometric amount ofeach is provided although, of course, excesses are acceptable.

Preferably, formulations in accordance with the present inventioninclude at least one pH adjusting substance. Without wishing to be boundby any particular theory, this permits a drug which is susceptible tochanges in ionization state can be administered by ensuring the properconditions for its dissolution as well as transmission across one ormore of the membranes or tissues within the oral cavity such as acrossthe oral mucosa. If the ideal conditions for transmission of aparticular drug are basic, the addition of a sufficient excess ofsuitably strong acid as part of the manufacture of an effervescentcouple or as a pH adjusting substance may not be indicated. Theselection of another pH adjusting substance such as, for example,anhydrous sodium carbonate which operates separate and apart from theeffervescent agents would be preferred.

pH adjusting substances in accordance with the present invention can beused to provide further permeation enhancement. The selection of theappropriate pH adjusting substance will depend on the drug to beadministered and, in particular, to the pH at which it is ionized orunionized, and whether the ionized or unionized form facilitatestransmission across the oral mucosa. With regard to fentanyl and itssalts, a basic substance is preferred for the delivery of fentanyl. pHadjusting substances in accordance with the present invention caninclude, without limitation, any substance capable of adjusting thelocalized pH to promote transport across the membranes in the oralcavity in amounts which will result in a pH's generally ranging frombetween about 3 to 10 and more preferably between about 4 to about 9.The pH is the “localized pH” at the microenvironment in the mouth of apatient at the surface contact area of the oral mucosa and the dosageform or any portion thereof (such as when it disintegrates). Forpurposes of this invention, the localized pH can, be determined asfollows: to characterize the dynamic pH changes displayed by the tabletsin question, an in vitro pH measurement was used. The method consists ofusing 0.5-10 mL of phosphate buffered saline in an appropriately sizedtest tube or similar vessel. The amount of media is dependent on thetablet size and dosage. For example, when measuring the pH profile forfentanyl tablets, a volume of 1 mL was used for tablets which weighed100 mg. Immediately upon tablet contact with the media, the pH profileof the solution is monitored as a function of time, using amicro-combination pH electrode. Preferably, the materials which can beused as pH adjusting substances in accordance with the present inventioninclude carbonates such as sodium, potassium or calcium carbonate or aphosphate such as calcium or sodium phosphate. Most preferred is sodiumcarbonate. The amount of pH adjusting substance useful in accordancewith the present invention can vary with the type of pH adjustingsubstance used, the amount of any excess acid or base from theeffervescent couple, the nature of the remaining ingredients and, ofcourse, the drug which, in this case, is fentanyl.

Most preferably the amount of pH adjusting substance will range frombetween about 0.5 to about 25 percent, more preferably between about 2to about 20 percent, even more preferably between about 5 to about 15percent and most preferably between about 7 to about 12 percent byweight based on the weight of the total formulation. The most preferredpH adjusting substance is a carbonate, bicarbonate, or phosphate. Alsopreferred are those pH adjusting substances which, when provided in asuitable amount, can provide a change in the localized pH of at leastabout 0.5 pH units, more preferably about 1.0 pH units and even morepreferably about 2.0 pH units when compared to an otherwise identicalformulation without the pH adjusting substance.

Any filler or any amount of a filler may be used as long as theresulting dosage forms achieve the results described herein. Mostpreferred amongst the fillers are sugar and sugar alcohols and these mayinclude non-direct compression and direct compression fillers.Non-direct compression fillers generally, at least when formulated, haveflow and/or compression characteristics which make them impractical foruse in high speed tableting process without augmentation or adjustment.For example, a formulation may not flow sufficiently well and therefore,a glidant such as, for example, silicon dioxide may need to be added.

Direct compression fillers, by contrast, do not require similarallowances. They generally have compressibility and flowabilitycharacteristics which allow them to be used directly. It is noted that,depending upon the method by which formulations are made, non-directcompression fillers may be imparted with the properties of directcompression fillers. The reverse is also true. As a general matter,non-direct compression fillers tend to have a relatively smallerparticle size when compared to direct compression fillers. However,certain fillers such as spray dried mannitol have relatively smallerparticle sizes and yet are often directly compressible, depending uponhow they are further processed. There are also relatively largenondirect compression fillers as well.

Fillers that are preferred in accordance with the present inventioninclude mannitol, lactose, sorbitol, dextrose, sucrose, xylitol andglucose, to the extent their use can provide the results describedherein. More preferably in accordance with the present invention, thefiller is not lactose monohydrate used in an amount of 20% or more basedon the weight of the formulation and even more preferably no lactosemonohydrate is used. Most preferred in accordance with the presentinvention, spray dried mannitol is used. The amount of filler can rangefrom 10 to about 80% and more preferably about 25 to about 80%, mostpreferably 35 to about 60% by weight of the formulation.

Disintegrants may also be used in accordance with the present inventionso long as they permit or even facilitate the dose reductions, linearityand/or ratio of Cmax and dose as described herein. These may alsoinclude binders that have disintegrating properties. Disintegrants inaccordance with the present invention can include microcrystallinecellulose, cross-linked polyvinyl pyrrolidone (PVP-XL), sodium starchglycolate, croscarmellose sodium, cross-linked hydroxypropyl celluloseand the like. Of course, the selection of the disintegrant depends uponwhether or not, in a given system, the results described herein may beobtained. More preferably, the formulation will be free of more thanabout 20% microcrystalline cellulose and cross-linked polyvinylpyrrolidone in an amount of about 5% or more, especially in aformulation that includes in additional 20% lactose monohydrate. Mostpreferred for use as a disintegrant is a starch glycolate and inparticular sodium starch glycolate. Indeed, it has been found that theuse of sodium starch glycolate in the formulations of the presentinvention can provide significant improvement in the degree of dosereduction, while still providing a comparable Cmax, when compared toeffervescent formulations which include pH adjusting substances andother disintegrants. A particularly useful sodium starch glycolate isGLYCOLYS® (standard grade) available from Roquette of Lestrem France.Indeed, it is even more preferred that the formulation include neithermicrocrystalline cellulose nor cross-linked PVP.

The amount of disintegrant will vary with known factors such as, thesize of the dosage form, the nature and amounts of the other ingredientsused, etc. However, in general the amount should range from betweenabout 0.25 to about 20% by weight of the final formulation, morepreferably between about 0.5 to about 15% w/w, even more preferably 0.5to about 10% w/w and even more preferably between about one and abouteight percent by weight. This is again based on the weight of thefinished formulation.

Also generally useful in accordance with the present invention is atableting or ejection lubricant. The most common known lubricant ismagnesium stearate and the use of magnesium stearate is preferred.Generally, the conventional wisdom behind tableting lubricants is thatless is more. It is preferred in most circumstances that less than aboutone percent of a tableting lubricant be used. Typically, the amountshould be half a percent or less. However, the amount of magnesiumstearate used can be greater than 1.0%. Indeed, it is preferably greaterthan about 1.5% and most preferably between about 1.5% and about 3%.Most preferred is the use of about 2% magnesium stearate. Otherconventional tableting lubricants such as, for example, stearic acid,calcium stearate and the like may also be used in place of some or allof the magnesium stearate.

Effervescent tablets in accordance with the present invention can berelatively soft or robust. They can, for example, be manufactured inaccordance with the methods described in U.S. Pat. No. 5,178,878 andwill have a hardness of generally less than about 15 Newtons. Unlike theformulations described in the '878 patent, the active ingredient herewill not necessarily be coated with a protective material. Indeed,preferentially, the fentanyl active will not be coated. When tablets assoft and pliable/friable as these are produced, they may beadvantageously packaged in a blister package such as found in U.S. Pat.No. 6,155,423. They may also be robust with a hardness of greater thanabout 15 newtons, manufactured in accordance with the procedures setforth in U.S. Pat. No. 6,024,981. In a preferred embodiment, thefentanyl dosage forms of the invention are provided in a blister packagewhich is child resistant. See for example U.S. Pat. No. 6,155,423 toKatzner et al., issued Dec. 5, 2000 and assigned to CIMA LABS INC., thetext of which is hereby incorporated by reference. Most preferably, thepackage meets the standards set forth in 16 U.S.C. §1700.15 and .20(2003). Packages also preferred include those commonly referred to inthe industry as so-called “F1” and “F2” packages. “F1” packages are mostpreferred.

Tablets in accordance with the present invention may be designedslightly differently for buccal, gingival, or sublingual administration.In each instance, however, the in mouth disintegration time/dissolution(dwell time) achieved by the formulations is preferably less than about30 minutes and most preferably, about 20 minutes or less. It is usuallymore than five minutes, most often 10 minutes or more. This is asubjective determination based on the response of the patient.

In accordance with a particularly preferred embodiment of the presentinvention, there is provided an effervescent orally disintegrable tabletdesigned for buccal, sublingual or gingival administration of fentanyl,or pharmaceutically acceptable salt thereof, comprising between about100 and about 800 micrograms of fentanyl (by weight based on the weightof the free base), an effective amount of an effervescent couple and aneffective amount of a pH adjusting substance and a starch glycolate. Theformulation may further include mannitol.

In a particularly preferred aspect of this embodiment of the presentinvention, the formulations described above do not include an amount oflactose monohydrate and/or cross-linked PVP which render it incapable ofobtaining a dose reduction relative to ACTIQ® of at least about 45%fentanyl by weight. In particular, it is preferred that no more thanabout 10% by weight of the formulation be lactose monohydrate ormicrocrystalline cellulose and no more than about 4% crosslinked PVP.More preferably, the formulation is free from all but incidental amountsof these excipients. Most preferred in accordance with the presentinvention are the use of sodium starch glycolate as a disintegrant andmannitol as a filler. Most preferred filler includes spray driedmannitol.

The formulations in accordance with the present invention can includeother conventional excipients in generally known amounts to the extentthey do not detract from the advantages described herein. These caninclude without limitation binders, sweeteners, coloring components,flavors, glidants, lubricants, preservatives, disintegrants, and thelike.

Tablets, a preferred dosage form in accordance with the presentinvention, can be made by any known tableting technique. However,preferably, the materials used are dry blended and directly compressed.While the tablets may result from granulation, this is not preferred. Ofcourse, particular excipients and materials used in formulations inaccordance with the present invention may be wet or dry granulated. Forexample, granulated mannitol could be used as a filler. It may also bedesirable to granulate or pre-mix some portion of the formulation priorto final blending and compression. The materials in question arepreselected to provide the right dose and content uniformity and thedose reduction, Cmax/dose ratio and/or dose linearity described herein.Thus, an appropriate amount of an effervescent couple, a suitable andappropriate pH adjusting substance and an appropriate disintegrant areselected, provided in predetermined amounts and formulated to dosageforms, preferably tablets.

The preferred pH adjusting substances are carbonates, bicarbonates, orphosphates, the preferred disintegrant is a starch glycolate. Theamounts used of each are described elsewhere herein. However,preferably, the disintegrant is selected and provided in an amount whichcan provide a further dose reduction in the amount of fentanyl used whencompared to an otherwise identical formulation containing aneffervescent couple and a pH adjusting substance without thedisintegrant. The pH adjusting substance preferably is selected andprovided in an amount sufficient which is capable of providing a changein localized pH of at least 0.5 pH units, more preferably 1.0 pH unitand most preferably about 2.0 pH units or more. While tablets may becompressed to any hardness and/or friability, same must be accomplishedwithout adversely affecting dwell times and drug release andtransmission across the oral mucosa. Where possible, it is desirable toprovide fentanyl dosage forms as compressed tablets having a hardness ofbetween about 5 and about 100 Newtons, more preferably between about 10and about 50 Newtons.

The dosage forms in accordance with the present invention may be used totreat any type of pain and in particular pain for which opiates arecommonly prescribed. As with all opiates, fentanyl products andparticularly those of the present invention should always be taken inconsultation with a doctor and under a physician's strict care andsupervision. The general directions for the use of the ACTIQ product asfound in the previously mentioned label found in the Physician's DeskReference and the warnings and contraindications therein are broadlyapplicable to the use of dosage forms in accordance with the presentinvention. This includes generally titrating patients with lower dosesbefore dose escalation.

The dosage forms in accordance with the present invention areadministered by being placed in the mouth of a patient, preferably underthe tongue or in between the cheek and gum, where they remain untiltheir dissolution/disintegration is substantially complete and theycease to be recognizable as a dosage form. Preferably, swallowing isminimized to assist in facilitating the maximum transfer of the fentanylacross the adjacent oral mucosa.

Additional doses are taken as needed. As previously noted, a single dosesuch as, for example, 800 micrograms of fentanyl, can be taken in asingle dosage form in accordance with the present invention or can betaken in a plurality of dosage forms such as, for example, two dosageforms of the present invention each containing 400 micrograms offentanyl or four dosage forms in accordance with the present inventioneach containing approximately 200 micrograms of fentanyl. Preferablysuch multiple dosage form dosing will involve all of the dosage formsbeing administered within an hour, more preferably roughlycontemporaneously if not simultaneously.

In particular, one method of making a tablet in accordance with thepresent invention useful for buccal, gingeval, or sublingualadministration comprises providing fentanyl or a salt thereof in anamount of between about 100 and about 800 micrograms per dose (measuredas fentanyl base), or an equivalent amount of salt thereof. Alsoprovided are an effervescent couple in an amount of 5 to about 85% byweight of the dosage form, at least one pH adjusting substance in anamount of between about 0.5 and about 25% by weight of the dosage formand at least one disintegrant, preferably a starch glycolate, providedin an amount between about 0.25 to about 20% by weight of the dosageform. These are blended and compressed into tablets. In a preferredembodiment, the filler is used as well. In a particular preferredembodiment, a portion of the filler may be preblended with the fentanylor another excipient such as, for example, a coloring agent.

In addition, one of the excipients often used in accordance with thepresent invention is a lubricant such as magnesium sterate. Generallythis is added toward the end of the blending period. Blending is ofteninterrupted and then magnesium sterate is added before blending resumesfor few additional minutes.

In a preferred embodiment, a blister package containing a dosage fromand in accordance with the present invention should be openedimmediately prior to the product's use. The patient should place thedosage form in his or her mouth, preferably between the cheek and theupper or lower gum. The dosage form should not be sucked or chewed.Fentanyl, as with many opiates, is preferably titrated with the initialdose being a relatively low dose. The initial dose for dosage forms forfentanyl formulations in accordance with the present invention,especially those used to treat episodes of breakthrough cancer pain,should be 100 micrograms. The patient should be provided with a limitedinitial titration supply of 100 microgram dosage forms, thus limitingthe number of units in the home during titration. Thereafter, doses maybe escalated under a doctor's care.

EXAMPLES

Method of Manufacture

In each case for examples 1-7 and 9-11, materials were screened prior touse, charged into a V-blender, or can be blended in any otherappropriate low shear blender, and blended for an appropriate time.After discharge from the blender, the materials were compressed on astandard rotary tablet press to a target hardness of 13 Newtons and atarget weight of 100 or 200 mg as described in each example.

Example 1 Form A

OraVescent® Fentanyl, 1080 mcg, 5/16″ Tablet, Red QUANTITY COMPONENTNAME (mg/tab) Fentanyl Citrate, USP 1.688 Mannitol, USP* 95.312 SodiumBicarbonate, USP/EP/JP 42.000 Citric Acid, USP/EP/JP 30.000 SodiumCarbonate, USP/NF 20.000 Sodium Starch Glycolate, NF/EP 6.000 MagnesiumStearate, NF/EP/JP 4.000 Red Ferric Oxide, NF 1.000 TOTAL 200.000*spray dried (Mannogem EX by SPI Pharma)

Example 2 Form C

OraVescent® Fentanyl, 1300 mcg, 5/16″ Tablet, Red QUANTITY COMPONENTNAME (mg/tab) Fentanyl Citrate, USP 2.042 Mannitol, USP* 94.958 SodiumBicarbonate, USP/EP/JP 42.000 Citric Acid, USP/EP/JP 30.000 SodiumCarbonate, USP/NF 20.000 Sodium Starch Glycolate, NF/EP 6.000 MagnesiumStearate, NF/EP/JP 4.000 Red Ferric Oxide, NF 1.000 TOTAL 200.000*spray dried

Example 3 Form D

OraVescent® Fentanyl, 810 mcg, 5/16″ Tablet, Yellow QUANTITY COMPONENTNAME (mg/tab) Fentanyl Citrate, USP 1.266 Mannitol, USP* 95.734 SodiumBicarbonate, USP/EP/JP 42.000 Citric Acid, USP/EP/JP 30.000 SodiumCarbonate, USP/NF 20.000 Sodium Starch Glycolate, NF/EP 6.000 MagnesiumStearate, NF/EP/JP 4.000 Yellow Ferric Oxide, NF 1.000 TOTAL 200.000*spray dried

Example 4 Form E

OraVescent® Fentanyl, 270 mcg, 5/16″ Tablet, White QUANTITY COMPONENTNAME (mg/tab) Fentanyl Citrate, USP 0.422 Mannitol, USP* 97.578 SodiumBicarbonate, USP/EP/JP 42.000 Citric Acid, USP/EP/JP 30.000 SodiumCarbonate, USP/NF 20.000 Sodium Starch Glycolate, NF/EP 6.000 MagnesiumStearate, NF/EP/JP 4.000 TOTAL 200.000*spray dried

Example 5

OraVescent® Fentanyl, 500 mcg, 5/16″ Tablet, Orange QUANTITY COMPONENTNAME (mg/tab) Fentanyl Citrate, USP 0.786 Mannitol, USP* 96.214 SodiumBicarbonate, USP/EP/JP 42.000 Citric Acid, USP/EP/JP 30.000 SodiumCarbonate, NF 20.000 Sodium Starch Glycolate, NF/EP 6.000 MagnesiumStearate, NF/EP/JP 4.000 Yellow Ferric Oxide, NF 0.600 Red Ferric Oxide,NF 0.400 TOTAL 200.000*spray dried

Example 6

OraVescent® Fentanyl, 200 mcg, 5/16″ Tablet, White QUANTITY COMPONENTNAME (mg/tab) Fentanyl Citrate, USP 0.315 Mannitol, USP* 97.685 SodiumBicarbonate, USP/EP/JP 42.000 Citric Acid, USP/EP/JP 30.000 SodiumCarbonate, NF 20.000 Sodium Starch Glycolate, NF/EP 6.000 MagnesiumStearate, NF/EP/JP 4.000 TOTAL 200.000*spray dried

Example 7

OraVescent® Fentanyl, 100 mcg, ¼″ Tablet, White QUANTITY COMPONENT NAME(mg/tab) Fentanyl Citrate, USP 0.157 Mannitol, USP* 48.843 SodiumBicarbonate, USP/EP/JP 21.000 Citric Acid, USP/EP/JP 15.000 SodiumCarbonate, NF 10.000 Sodium Starch Glycolate, NF/EP 3.000 MagnesiumStearate, NF/EP/JP 2.000 TOTAL 100.000*spray dried

Example 8

The materials may be screened prior to use, charged into a V-blender orother appropriate low shear blender, and blended for an appropriatetime. After discharge from the blender, the materials may be compressedon a standard rotary tablet press to a target hardness of 13 Newtons anda target weight of 200 mg/tablet.

OraVescent® Fentanyl, 300 mcg, 5/16″ Tablet, Light Yellow QUANTITYCOMPONENT NAME (mg/tab) Fentanyl Citrate, USP 0.472 Mannitol, USP*97.328 Sodium Bicarbonate, USP/EP/JP 42.000 Citric Acid, USP/EP/JP30.000 Sodium Carbonate, NF 20.000 Sodium Starch Glycolate, NF/EP 6.000Magnesium Stearate, NF/EP/JP 4.000 Yellow Ferric Oxide, NF 0.200 TOTAL200.000*spray dried

Example 9

OraVescent® Fentanyl, 400 mcg, 5/16″ Tablet, Pink QUANTITY COMPONENTNAME (mg/tab) Fentanyl Citrate, USP 0.629 Mannitol, USP* 97.171 SodiumBicarbonate, USP/EP/JP 42.000 Citric Acid, USP/EP/JP 30.000 SodiumCarbonate, NF 20.000 Sodium Starch Glycolate, NF/EP 6.000 MagnesiumStearate, NF/EP/JP 4.000 Red Ferric Oxide, NF 0.200 TOTAL 200.000*spray dried

Example 10

OraVescent® Fentanyl, 600 mcg, 5/16″ Tablet, Orange QUANTITY COMPONENTNAME (mg/tab) Fentanyl Citrate, USP 0.943 Mannitol, USP* 96.057 SodiumBicarbonate, USP/EP/JP 42.000 Citric Acid, USP/EP/JP 30.000 SodiumCarbonate, NF 20.000 Sodium Starch Glycolate, NF/EP 6.000 MagnesiumStearate, NF/EP/JP 4.000 Yellow Ferric Oxide, NF 0.600 Red Ferric Oxide,NF 0.400 TOTAL 200.000*spray dried

Example 11

OraVescent® Fentanyl, 800 mcg, 5/16″ Tablet, Yellow QUANTITY COMPONENTNAME (mg/tab) Fentanyl Citrate, USP 1.257 Mannitol, USP* 95.743 SodiumBicarbonate, USP/EP/JP 42.000 Citric Acid, USP/EP/JP 30.000 SodiumCarbonate, NF 20.000 Sodium Starch Glycolate, NF/EP 6.000 MagnesiumStearate, NF/EP/JP 4.000 Yellow Ferric Oxide, NF 1.000 TOTAL 200.000*spray dried

Example 12

The following materials are weighed and screened. Qty./Tablet Qty./Batch# Description (% w/w) (kg) 1 Fentanyl Citrate 0.6285 502.8 g* 2a.Mannitol EZ 23.875 19.1 2b. Mannitol EZ 24.014 19.2 3. SodiumBicarbonate, No. 1 21.0000 16.8 4. Citric Acid, Anhydrous, 15.0000 12.0Fine Granular 5. Sodium Carbonate, 10.0000 8.000 Anhydrous 6. SodiumStarch Glycolate 3.0000 2.400 7. Yellow 10 Iron Oxide 0.5000 0.400 8.Magnesium Stearate, Non- 2.0000 1.600 Bovine Total 100.0000 80.0

Transfer Mannitol EZ (2a.) and Yellow 10 Iron Oxide to V-blender andblend for 30 minutes. Discharge and mill preblend. Add the totalquantity of preblend, fentanyl citrate, sodium bicarbonate, citric acid,sodium carbonate and sodium starch glycolate to V-blender and blend for30 minutes. Charge Mannitol (2b) into V-blender and blend for 13minutes. Charge magnesium stearate into V-blender and blend for 5minutes. Compress tablets from this final blend. These tablets are ¼″round, flat faced, white with a beveled edge. They are compressed to anaverage hardness of 13 Newtons on a 36 station Fette tablet press fullytooled.

1. A dosage form comprising: about 100 to about 800 micrograms offentanyl, calculated as fentanyl free base or an equivalent amount of asalt thereof, an effervescent couple in an amount of about 5 to about85% by weight of the dosage form, a pH adjusting substance in an amountof about 0.5 to about 25% by weight of the dosage form, and a starchglycolate in an amount of about 0.25 to about 20% by weight of thedosage form, said dosage form being suitable for delivery of saidfentanyl across the oral mucosa of a patient by buccal, gingival orsublingual administration.
 2. The dosage form of claim 1 wherein said pHadjusting substance is selected and provided in an amount capable ofproviding a change in localized pH of at least 0.5 pH units.
 3. Thedosage form of claim 2 wherein said pH adjusting substance is acarbonate or bicarbonate.
 4. The dosage form of claim 1 furthercomprising a filler.
 5. The dosage form of claim 4 wherein said filleris present in an amount of between about 10 and about 80% w/w.
 6. Thedosage form of claim 4 wherein said filler is mannitol.
 7. The dosageform of claim 1 being a compressed tablet.
 8. The dosage form of claim 1having a C_(max) which is comparable to that of an ACTIQ® dosage formhaving about 80% more fentanyl
 9. The dosage form of claim 8 having aC_(max) which is highly comparable to that of an ACTIQ® dosage formhaving about 80% more fentanyl.
 10. The dosage form of claim 9 having aC_(max) which is very highly comparable to that of an ACTIQ® dosage formhaving about 80% more fentanyl.
 11. The dosage form of claim 1 having alinear relationship between dose and C_(max).
 12. The dosage form ofclaim 1 wherein the ratio of C_(max) to dose is between about 2.0 andabout 4.0 picograms/mL/microgram.
 13. The dosage form of claim 12wherein the ratio of C_(max) to dose is between about 2.5 and about 3.5picograms/mL/microgram.
 14. The dosage form of claim 13 wherein theratio of C_(max) to dose is between about 2.7 and about 3.5picograms/mL/microgram.
 15. A dosage form comprising: about 100 to about800 micrograms of fentanyl, calculated as fentanyl free base or anequivalent amount of a salt thereof, an effervescent couple, a pHadjusting substance said adjusting substance selected and provided in anamount capable of providing a change in localized pH of at least 0.5 pHunits, and a starch glycolate, said dosage form being suitable fordelivery of said fentanyl across the oral mucosa of a patient by buccal,gingival or sublingual administration and providing a ratio of C_(max)to dose is between about 2.0 and about 4.0 picograms/mL/microgram, alinear relationship between dose and C_(max), or a C_(max) which iscomparable to that of an ACTIQ® dosage form having about 80% morefentanyl.
 16. The dosage form of claim 15 providing a ratio of C_(max)to dose is between about 2.7 and about 3.5 picograms/mL/microgram. 17.The dosage form of claim 16 further providing a linear relationshipbetween dose and C_(max).
 18. The dosage form of claim 15 providing aC_(max) which is comparable to that of an ACTIQ® dosage form havingabout 80% more fentanyl.
 19. The dosage form of claim 18 furtherproviding a linear relationship between dose and C_(max).
 20. The dosageform of any one of claims 15, 17 and 19 wherein said effervescent coupleis present in an amount of about 5 to about 85% by weight of said dosageform, said pH adjusting substance is present in an amount of about 0.5to about 25% by weight of said dosage form, and said starch glycolate ispresent in an amount of about 0.25 to about 20% by weight of the dosageform.
 21. The dosage form of claim 20 wherein said effervescent coupleis present in an amount of about 15 to about 60% by weight of saiddosage form, said pH adjusting substance is present in an amount ofabout 2 to about 20% by weight of said dosage form, and said starchglycolate is present in an amount of about 0.5 to about 15% by weight ofthe dosage form.
 22. The dosage form of claim 20 further comprising afiller.
 23. The dosage form of claim 22 wherein said filler is presentin an amount of between about 10 and about 80% w/w.
 24. The dosage formof claim 23 wherein said filler is mannitol.
 25. The dosage form ofclaims 1 or 15 packaged in an F1 package.
 26. A method of treating painin a patient in need thereof comprising the steps of: placing a dosageform comprising about 100 to about 800 micrograms of fentanyl,calculated as fentanyl free base or an equivalent amount of a saltthereof, an effervescent couple, a pH adjusting substance said adjustingsubstance selected and provided in an amount capable of providing achange in localized pH of at least 0.5 pH units, and a starch glycolate,said dosage form being suitable for delivery of said fentanyl across theoral mucosa of a patient by buccal, gingival or sublingualadministration and providing a ratio of C_(max) to dose is between about2.0 and about 4.0 picograms/mL/microgram, a linear relationship betweendose and C_(max), or a C_(max) which is comparable to that of an ACTIQ®dosage form having about 80% more fentanyl into the mouth of a patientin contact with said patient's oral mucosa, and maintaining said dosageform in intimate contact with said oral mucosa for a time sufficient todeliver a therapeutically effective amount of said fentanyl across saidoral mucosa.
 27. The method of claim 26 wherein said dosage form is heldin contact with said oral mucosa for a period of between about 10 andabout 30 minutes.
 28. The method of claim 26 wherein said dosage form isheld in contact with said oral mucosa for a period of time sufficient toprovide absorption of at least about 75% of said fentanyl dose into theblood stream of said patient.
 29. The method of claim 26 wherein saidpain is selected from the group consisting of breakthrough cancer pain,back pain, neuropathic pain, surgical pain, or post operative pain. 30.A method of treating episodes of breakthrough cancer pain comprising thesteps of providing an initial dose of about 100 micrograms of fentanylcalculated as a fentanyl free base or an equivalent amount of a saltthereof, in a dosage form comprising an effervescent couple in amount ofabout 5 to about 85% by weight of the dosage form, a pH adjustingsubstance in an amount of about 0.5 to about 25% by weight of the dosageform, and a starch glycolate in the amount of 0.25 to about 20% byweight of the dosage form, said dosage form being suitable for deliveryof said fentanyl across the oral mucosa of a patient, and placing saiddosage form in the mouth of said patient between the cheek and the upperor lower gum, for a time sufficient to deliver a therapeuticallyeffective amount of said fentanyl across said oral mucosa.